Mercaptoimidazoles as ccr2 receptor antagonists

ABSTRACT

The present invention relates to a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R 1  represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxyC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, aryl or heteroaryl; each R 2  independently represents halo, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, cyano, aminocarbonyl, amino, mono- or di(C 1-4 alkyl)amino, nitro, aryl or aryloxy; R 3  represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b  or C(═O)—R 8 ; R 4  represents hydrogen, cyano, C 1-6 alkyl optionally substituted with hydroxy or C 1-6 alkyloxy, C(═O)—O—R 6 , C(═O)—NR 7a R 7b , C(═S)—NR 7a R 7b , S(═O) 2 —NR 7a R 7b  or C(═O)—R 8 ; or R 3  and R 4  taken together may form a bivalent radical of formula —C(═O)—NH—NH—C(═O)—; n is 1, 2, 3, 4 or 5;
 
provided
 
that at least one of R 3  or R 4  is other than hydrogen; and that if R 3  represents C(═O)—OH, C(═O)—O—C 1-6 alkyl or C(═O)—O—C 2-6 alkenyl, then R 4  is other than hydrogen; and that if R 3  represents CH 2 OH and R 1  and R 5  represents hydrogen, then R 4  is other than hydrogen; and that if R 3  represents C(═O)—NH—C 1-4 alkyl-NH 2  and R 1  and R 5  represents hydrogen, then R 4  is other than hydrogen; and that if R 3  represents
 
     
       
         
         
             
             
         
       
     
     and R 1  and R 5  represents hydrogen, then R 4  is other than hydrogen having CCR2 receptor antagonistic properties. The invention also relates to processes for preparing the compounds of formula (1) and pharmaceutical compositions comprising them.

The present invention concerns mercaptoimidazole derivatives having CCR2receptor antagonistic properties. The invention further relates tomethods for their preparation and pharmaceutical compositions comprisingthem. The invention also relates to the use of said compounds for themanufacture of a medicament for the prevention or the treatment ofdiseases mediated through activation of the CCR2 receptor, in particularthe CCR2B receptor.

EP 0,240,050 discloses 1-methyl-1H-imidazole-5-carboxylic acidderivatives for controlling weeds.

U.S. Pat. No. 3,354,173 discloses imidazole carboxylates as hypnotics.

U.S. Pat. No. 4,182,624 discloses benzhydryl-imidazole derivativeshaving carboxyl functions in the imidazole ring. The compounds aredescribed as having valuable properties in plant protection and growthregulation in agriculture and horticulture.

EP 0,000,373 relates to imidazole carbonic acid derivatives and theiruse for plant protection.

WO 01/17974 and Organic Process Research and Development, 2002, 6(5),674-676 relates to the synthesis of 1 substituted5-(hydroxymethyl)imidazole derivatives.

WO 00/75135 describes biaryl inhibitors of prenyl-protein transferase.

Arzneimittel-Forschung, 1980, 30(7), 1051-1056 describes imidazolederivatives with potential biological activity.

U.S. Pat. No. 4,762,850 relates to2-mercapto-1-(phenylalkyl)-1H-imidazole-5-carboxylic acid derivatives asdopamine β-hydroxylase inhibitors.

EP 294,973 relates to 1-aralkyl-5-(piperazinomethyl)-imidazole-2-thiolsas dopamine β-hydroxylase inhibitors.

DE 2,618,370 relates to imidazo[5,1-c](1,4)-benzoxazepines and theirpreparation.

EP 146,228 describes substituted 2-mercapto-imidazoles useful in thepreparation of phenylethylimidazole derivatives of therapeutic interest.

WO 01/09127, WO 01/09124 and WO 99/41248 relates to condensedheterocyclic system derivatives as farnesyl transferase inhibitors.

WO 00/01674 relates to the preparation of 1-benzylimidazoles frombenzylamines, hydroxyketones and thiocyanates.

WO 92/10182, WO 92/10186, WO 92/10188 and EP 437,103 concern imidazolederivatives as intermediates in the preparation of angiotensin IIreceptor antagonists. J. Heterocyclic Chemistry, 1982, 19(3), 561-566concerns the synthesis of imidazole derivatives with potentialbiological activity.

WO 02/066458 concerns 2-thio-substituted imidazole derivatives useful totreat diseases which are related to the dysfunction of the immunesystem.

FR 1487326 and FR 6751 discloses imidazole derivatives as sedatives andanalgesics.

WO 01/05430 describes the preparation of1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone as model drug for sustained release in a drugdelivery device.

WO 99/40913 provides substituted pyrroles which are inhibitors ofmonocyte chemoattractant protein-1 and WO 01/51466 relates to indolederivatives as MCP-1 receptor antagonists.

The compounds of the invention differ from the prior art compounds instructure, in that they exert a pharmaceutical activity, in theirpharmacological activity and/or pharmacological potency.

One aspect of the present invention relates to a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein

-   R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl or    heteroaryl;-   each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    C₁₋₆alkylthio, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano,    aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, nitro, aryl or    aryloxy;-   R₃ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₅;-   R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   or R₃ and R₄ taken together may form a bivalent radical of formula    —C(═O)—NH—NH—C(═O)—;-   R₆ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or    di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl, aryl, pyrrolidinyl,    imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl    or thiomorpholinyl; wherein pyrrolidinyl, imidazolidinyl,    pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or    thiomorpholinyl may optionally be substituted with C₁₋₄alkyl;-   R_(7a) and R_(7b) each independently represent hydrogen, C₁₋₆alkyl,    amino, mono- or di(C₁₋₄alkyl)amino, arylNH—, aminoC₁₋₆alkyl, mono-    or di(C₁₋₄alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonylamino,    aminocarbonylamino, C₁₋₆alkyloxy, —NH—C(O)—H or hydroxyC₁₋₆alkyl; or-   R_(7a) and R_(7b) taken together with the nitrogen to which they are    attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl,    piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or    piperazinyl substituted with C₁₋₆alkyl;-   R₈ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl    or aryl;-   R₅ represents hydrogen or C₁₋₆alkyl;-   n is 1, 2, 3, 4 or 5;-   aryl represents phenyl or phenyl substituted with one, two, three,    four or five substituents each independently selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    cyano, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, amino,    mono- or di(C₁₋₄alkyl)amino, phenyloxy or nitro;-   heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl,    thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,    oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, each of said heterocycles optionally being    substituted with one or two substituents each independently selected    from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy, cyano, aminocarbonyl, mono- or    di(C₁₋₄alkyl)aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino or    nitro;    provided    that at least one of R₃ or R₄ is other than hydrogen; and    that if R₃ represents C(═O)—OH, C(═O)—O—C₁₋₆alkyl or    C(═O)—O—C₂₋₆alkenyl, then R₄ is other than hydrogen; and    that if R₃ represents CH₂OH and R₁ and R₅ represent hydrogen, then    R₄ is other than hydrogen; and    that if R₃ represents C(═O)—NH—C₁₋₄alkyl-NH₂ and R₁, and R₅    represents hydrogen, then R₄ is other than hydrogen; and that if R₃    represents

and R₁ and R₅ represents hydrogen, then R₄ is other than hydrogen.

The present invention also relates to a compound of formula (I) asdefined above for use as a medicine

providedthat at least one of R₃ or R₄ is other than hydrogen; andthat if R₃ represents C(═O)—OH or C(═O)—O—C₁₋₆alkyl; R₁ represents aryland n is 1, then R₄ is other than hydrogen; andthat if R₃ represents C(═O)—NH—C₁₋₄alkyl-NH₂ or C(═O)—OH and R₁ and R₅represent hydrogen, then R₄ is other than hydrogen.

Thus, the present invention also relates to a compound for use as amedicine wherein the compound is a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein

-   R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl or    heteroaryl;-   each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    C₁₋₆alkylthio, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano,    aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, nitro, aryl or    aryloxy;-   R₃ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   or R₃ and R₄ taken together may form a bivalent radical of formula    —C(═O)—NH—NH—C(═O)—;-   R₆ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or    di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl, aryl, pyrrolidinyl,    imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl    or thiomorpholinyl; wherein pyrrolidinyl, imidazolidinyl,    pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or    thiomorpholinyl may optionally be substituted with C₁₋₄alkyl;-   R_(7a) and R_(7b) each independently represent hydrogen, C₁₋₆alkyl,    amino, mono- or di(C₁₋₄alkyl)amino, arylNH—, aminoC₁₋₆alkyl, mono-    or di(C₁₋₄alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonylamino,    aminocarbonylamino, C₁₋₆alkyloxy, —NH—C(O)—H or hydroxyC₁₋₆alkyl; or-   R_(7a) and R_(7b) taken together with the nitrogen to which they are    attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl,    piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or    piperazinyl substituted with C₁₋₆alkyl;-   R₈ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl    or aryl;-   R₅ represents hydrogen or C₁₋₆alkyl;-   n is 1, 2, 3, 4 or 5;-   aryl represents phenyl or phenyl substituted with one, two, three,    four or five substituents each independently selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    cyano, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, amino,    mono- or di(C₁₋₄alkyl)amino, phenyloxy or nitro;-   heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl,    thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,    oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, each of said heterocycles optionally being    substituted with one or two substituents each independently selected    from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy, cyano, aminocarbonyl, mono- or    di(C₁₋₄alkyl)aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino or    nitro;    provided    that at least one of R₃ or R₄ is other than hydrogen; and    that if R₃ represents C(═O)—OH or C(═O)—O—C₁₋₆alkyl; R₁ represents    aryl and n is 1, then R₄ is other than hydrogen; and    that if R₃ represents C(═O)—NH—C₁₋₄alkyl-NH₂ or C(═O)—OH and R₁ and    R₅ represent hydrogen, then R₄ is other than hydrogen.

Another aspect of the present invention is the use of the compounds offormula (I) as defined above for the manufacture of a medicament forpreventing or treating diseases mediated through activation of the CCR2receptor, in particular for preventing or treating inflammatorydiseases.

Thus, the present invention also relates to the use of a compound forthe manufacture of a medicament for preventing or treating diseasesmediated through activation of the CCR2 receptor, in particular forpreventing or treating inflammatory diseases, wherein said compound is acompound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein

-   R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl or    heteroaryl;-   each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    C₁₋₆alkylthio, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano,    aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, nitro, aryl or    aryloxy;-   R₃ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted with    hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   or R₃ and R₄ taken together may form a bivalent radical of formula    —C(═O)—NH—NH—C(═O)—;-   R₆ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or    di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl, aryl, pyrrolidinyl,    imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl    or thiomorpholinyl; wherein pyrrolidinyl, imidazolidinyl,    pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or    thiomorpholinyl may optionally be substituted with C₁₋₄alkyl;-   R_(7a) and R_(7b) each independently represent hydrogen, C₁₋₆alkyl,    amino, mono- or di(C₁₋₄alkyl)amino, arylNH—, aminoC₁₋₆alkyl, mono-    or di(C₁₋₄alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonylamino,    aminocarbonylamino, C₁₋₆alkyloxy, —NH—C(O)—H or hydroxyC₁₋₆alkyl; or-   R_(7a) and R_(7b) taken together with the nitrogen to which they are    attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl,    piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or    piperazinyl substituted with C₁₋₆alkyl;-   R₈ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl,    aminocarbonylC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl    or aryl;-   R₅ represents hydrogen or C₁₋₆alkyl;-   n is 1, 2, 3, 4 or 5;-   aryl represents phenyl or phenyl substituted with one, two, three,    four or five substituents each independently selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    cyano, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, amino,    mono- or di(C₁₋₄alkyl)amino, phenyloxy or nitro; heteroaryl    represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,    imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,    triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,    pyrazinyl, each of said heterocycles optionally being substituted    with one or two substituents each independently selected from halo,    C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    cyano, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, amino,    mono- or di(C₁₋₄alkyl)amino or nitro;    provided    that at least one of R₃ or R₄ is other than hydrogen.

As used hereinbefore or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl; C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl and the like; C₃₋₇cycloalkyl is generic tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 6 carbon atoms containing a double bond such asethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C₂₋₆alkynyldefines straight and branched chain hydrocarbon radicals having from 2to 6 carbon atoms containing a triple bond such as ethynyl, propynyl,butynyl, pentynyl, hexynyl and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing or hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in polyhalomethyl, 1,1-difluoro-ethyl and the like. Incase more than one halogen atoms are attached to an alkyl group withinthe definition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be thesame or different.

The term heteroaryl in the definition of R₁ is meant to include all thepossible isomeric forms of the heterocycles, for instance, pyrrolylcomprises 1H-pyrrolyl and 2H-pyrrolyl.

The aryl, heteroaryl or heterocyclic ring systems listed in thedefinitions of the substituents of the compounds of formula (I) (see forinstance R₁ and R₆) as mentioned hereinabove or hereinafter may beattached to the remainder of the molecule of formula (I) through anyring carbon or heteroatom as appropriate, if not otherwise specified.Thus, for example, when heteroaryl is imidazolyl, it may be1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

When any variable (eg. R_(7a), R_(7b)) occurs more than one time in anyconstituent, each definition is independent.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely the salt form can be convertedby treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Thus, when a compound of formula (I) is for instancespecified as (E), this means that the compound is substantially free ofthe (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or transconfiguration. Compounds encompassing doublebonds can have an E (entgegen) or Z (zusammen)-stereochemistry at saiddouble bond. The terms cis, trans, R, S, E and Z are well known to aperson skilled in the art.

Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

For some of the compounds of formula (I), their N-oxides, salts,solvates, quaternary amines and the intermediates used in thepreparation thereof, the absolute stereochemical configuration was notexperimentally determined. In these cases the stereoisomeric form whichwas first isolated is designated as “A” and the second as “B”, withoutfurther reference to the actual stereochemical configuration. However,said “A” and “B” stereoisomeric forms can be unambiguously characterizedby for instance their optical rotation in case “A” and “B” have anenantiomeric relationship. A person skilled in the art is able todetermine the absolute configuration of such compounds using art-knownmethods such as, for example, X-ray diffraction. In case “A” and “B” arestereoisomeric mixtures, they can be further separated whereby therespective first fractions isolated are designated “A1” and “B1” and thesecond as “A2” and “B2”, without further reference to the actualstereochemical configuration.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formula(I) are intended to be included within the scope of the presentinvention. For instance, it is intended that formula (I) includes thetautomeric form of

being

Thus, the compounds of the present invention include compounds offormula

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their salts, their quaternaryamines and their stereochemically isomeric forms. Of special interestare those compounds of formula (I) which are stereochemically pure.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, suchas for example for R_(7a) or R_(7b), all possible combinations areintended which are chemically possible.

A first group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl or    heteroaryl;-   b) R₃ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b),    C(═O)—R₈;-   c) R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b),    C(═O)—R₈;-   d) R_(7a) and R_(7b) each independently represent hydrogen,    C₁₋₆alkyl, amino, mono- or di(C₁₋₄alkyl)amino, arylNH—,    aminoC₁₋₆alkyl or mono- or di(C₁₋₄alkyl)amino C₁₋₆alkyl; or R_(7a)    and R_(7b) taken together with the nitrogen to which they are    attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl,    piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl; and-   e) R₅ represents hydrogen;

A second group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy or    polyhaloC₁₋₆alkyl;-   b) R₃ represents hydrogen, cyano, C₁₋₆alkyl substituted with    hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b), C(═S)—NR_(7a)R_(7b) or    C(═O)—R₈;-   c) R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b);-   d) R₃ and R₄ taken together may form a bivalent radical of formula    —C(═O)—NH—NH—C(═O)—;-   e) R₆ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl or mono- or    di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl;-   f) R_(7a) and R_(7b) each independently represent hydrogen,    C₁₋₆alkyl, amino, C₁₋₆alkylcarbonylamino, aminocarbonylamino,    C₁₋₆alkyloxy, —NH—C(O)—H or hydroxyC₁₋₆alkyl; or R_(7a) and R_(7b)    taken together with the nitrogen to which they are attached form    pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or piperazinyl    substituted with C₁₋₆alkyl;-   g) R₈ represents C₁₋₆alkyl; and-   h)_(n) is 1, 2 or 3.

A third group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl or    heteroaryl;-   b) each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy or    polyhaloC₁₋₆alkyl;-   c) R₃ represents hydrogen, cyano, C₁₋₆alkyl substituted with    hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) or C(═O)—R₅;-   d) R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b);-   e) R₆ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl or mono- or    di(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl;-   f) R_(7a) and R_(7b) each independently represent hydrogen,    C₁₋₆alkyl, amino; or R_(7a) and R_(7b) taken together with the    nitrogen to which they are attached form pyrrolidinyl, piperidinyl,    piperazinyl or morpholinyl;-   g) R₈ represents C₁₋₆alkyl;-   h) n is 1, 2 or 3; and-   i) R₅ is hydrogen.

A fourth group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) R₁ represents C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl or heteroaryl;-   b) R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl or heteroaryl;-   c) each R₂ independently represents halo, C₁₋₆alkyl, C₁₋₆alkyloxy,    C₁₋₆alkylthio, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino, nitro, aryl or    aryloxy;-   d) R₃ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   e) if R₄ is hydrogen then R₃ represents cyano, C₁₋₆alkyl optionally    substituted with C₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),    C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈;-   f) R₃ and R₄ each independently represent hydrogen, cyano,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C(═O)—O—R₆,    C(═O)—NR_(7a)R_(7b), C(═S)—NR_(7a)R_(7b), S(═O)₂—NR_(7a)R_(7b) or    C(═O)—R₈; g) if R₃ represents C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b) then    R₁ is hydrogen, C₁₋₆alkyl,    -   C₃₋₇cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        di(C₁₋₆alkyl)aminoC₁₋₆alkyl or heteroaryl.

A fifth group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) R₁ represents hydrogen, C₁₋₆alkyl, cyclopropyl, cyclohexyl,    C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, phenyl or phenyl    substituted with two substituents each independently selected from    halo; in particular C₁₋₆alkyl;-   b) n is 1, 2 and 3; in particular n is 2 and said two R₂    substituents are placed in position 3 and 4;-   c) each R₂ independently represents halo or polyhaloC₁₋₆alkyl, in    particular halo;-   d) R₃ represents hydrogen, cyano, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) or    C(═O)—R₈; in particular C(═O)—O—R₆;-   e) R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy or C₁₋₆alkyloxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); in    particular C(═O)—O—R₆;-   f) R₃ and R₄ taken together may form a bivalent radical of formula    —C(═O)—NH—NH—C(═O)—;-   g) R₆ represents hydrogen, C₁₋₆alkyl or hydroxyC₁₋₆alkyl; in    particular C₁₋₆alkyl;-   h) R_(7a) represent hydrogen or C₁₋₆alkyl; and R_(7b) represents    hydrogen, C₁₋₆alkyl, amino, C₁₋₆alkylcarbonylamino, C₁₋₆alkyloxy or    hydroxyC₁₋₆alkyl; or R_(7a) and R_(7b) taken together with the    nitrogen to which they are attached form piperidinyl;-   i) R₈ represents C₁₋₆alkyl;-   j) R₅ is hydrogen.

A sixth group of interesting compounds consists of those compounds offormula (I) wherein one or more of the following restrictions apply:

-   a) R₁ represents hydrogen, C₁₋₆alkyl, cyclopropyl, cyclohexyl,    phenyl or phenyl substituted with two substituents each    independently selected from halo; in particular C₁₋₆alkyl;-   b) n is 1, 2 and 3; in particular n is 2 and said two R₂    substituents are placed in position 3 and 4;-   c) each R₂ independently represents halo or polyhaloC₁₋₆alkyl, in    particular halo;-   d) R₃ represents hydrogen, cyano, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) or    C(═O)—R₈; in particular C(═O)—O—R₆;-   e) R₄ represents hydrogen, cyano, C₁₋₆alkyl optionally substituted    with hydroxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); in particular    C(═O)—O—R₆;-   f) R₆ represents hydrogen, C₁₋₆alkyl or hydroxyC₁₋₆alkyl; in    particular C₁₋₆alkyl;-   g) R_(7a) represent hydrogen or C₁₋₆alkyl; and R_(7b) represents    hydrogen, C₁₋₆alkyl or amino; or R_(7a) and R_(7b) taken together    with the nitrogen to which they are attached form piperidinyl;-   h) R₈ represents C₁₋₆alkyl and-   i) R₅ is hydrogen.

A seventh group of interesting compounds consists of those compounds offormula (I) wherein both R₃ and R₄ are other than hydrogen.

An eight group of interesting compounds consists of those compounds offormula (I) wherein R₄ is hydrogen and R₃ is other than hydrogen; inparticular R₃ represents cyano, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) orC(═O)—R₈.

A ninth group of interesting compounds consists of those compounds offormula (I) wherein R₃ is hydrogen and R₄ is other than hydrogen, inparticular R₄ is cyano, C₁₋₆alkyl optionally substituted with hydroxy orC₁₋₆alkyloxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b).

A tenth group of interesting compounds consists of those compounds offormula (I) wherein R₃ is other than C(═O)—O—R₆ when R₄ is hydrogen.

An eleventh group of interesting compounds consists of those compoundsof formula (I) wherein R₃ is hydrogen.

A group of preferred compounds consists of those compounds of formula(I) wherein R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl orheteroaryl; R₃ represents hydrogen, cyano, C₁₋₆alkyl optionallysubstituted with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),S(═O)₂—NR_(7a)R_(7b), C(═O)—R₈; R₄ represents hydrogen, cyano, C₁₋₆alkyloptionally substituted with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),S(═O)₂—NR_(7a)R_(7b), C(═O)—R₈; R_(7a) and R_(7b) each independentlyrepresent hydrogen, C₁₋₆alkyl, amino, mono- or di(C₁₋₄alkyl)amino,arylNH—, aminoC₁₋₆alkyl or mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl; orR_(7a) and R_(7b) taken together with the nitrogen to which they areattached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl; and R₅ represents hydrogen.

Another group of preferred compounds consists of those compounds offormula (I) wherein each R₂ independently represents halo, C₁₋₆alkyl,C₁₋₆alkyloxy or polyhaloC₁₋₆alkyl; R₃ represents hydrogen, cyano,C₁₋₆alkyl substituted with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b),C(═S)—NR_(7a)R_(7b) or C(═O)—R₈; R₄ represents hydrogen, cyano,C₁₋₆alkyl optionally substituted with hydroxy or C₁₋₆alkyloxy,C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); R₃ and R₄ taken together may form abivalent radical of formula —C(═O)—NH—NH—C(═O)—; R₆ represents hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl or mono- ordi(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl; R_(7a) and R_(7b) eachindependently represent hydrogen, C₁₋₆alkyl, amino,C₁₋₆alkylcarbonylamino, aminocarbonylamino, C₁₋₆alkyloxy, —NH—C(O)—H orhydroxyC₁₋₆alkyl; or R_(7a) and R_(7b) taken together with the nitrogento which they are attached form pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl or piperazinyl substituted with C₁₋₆alkyl; R₈ representsC₁₋₆alkyl; and n is 1, 2 or 3.

A further group of preferred compounds consists of those compounds offormula (I) wherein R₁ represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,aryl or heteroaryl; each R₂ independently represents halo, C₁₋₆alkyl,C₁₋₆alkyloxy or polyhaloC₁₋₆alkyl; R₃ represents hydrogen, cyano,C₁₋₆alkyl substituted with hydroxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) orC(═O)—R₈; R₄ represents hydrogen, cyano, C₁₋₆alkyl optionallysubstituted with hydroxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); R₆represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl or mono- ordi(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl; R_(7a) and R_(7b) eachindependently represent hydrogen, C₁₋₆alkyl, amino; or R_(7a) and R_(7b)taken together with the nitrogen to which they are attached formpyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; R₈ representsC₁₋₆alkyl; n is 1, 2 or 3; and R₅ represents hydrogen.

A group of more preferred compounds consists of those compounds offormula (I) wherein R₁ represents hydrogen, C₁₋₆alkyl, cyclopropyl,cyclohexyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, phenylor phenyl substituted with two substituents each independently selectedfrom halo; n is 1, 2 and 3; each R₂ independently represents halo orpolyhaloC₁₋₆alkyl; R₃ represents hydrogen, cyano, C(═O)—O—R₆,C(═O)—NR_(7a)R_(7b) or C(═O)—R₈; R₄ represents hydrogen, cyano,C₁₋₆alkyl optionally substituted with hydroxy or C₁₋₆alkyloxy,C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); R₃ and R₄ taken together may form abivalent radical of formula —C(═O)—NH—NH—C(═O)—; R₆ represents hydrogen,C₁₋₆alkyl or hydroxyC₁₋₆alkyl; R_(7a) represent hydrogen or C₁₋₆alkyl;and R_(7b) represents hydrogen, C₁₋₆alkyl, amino,C₁₋₆alkylcarbonylamino, C₁₋₆alkyloxy or hydroxyC₁₋₆alkyl; or R_(7a) andR_(7b) taken together with the nitrogen to which they are attached formpiperidinyl; R₈ represents C₁₋₆alkyl; and R₅ represents hydrogen.

A group of more preferred compounds consists of those compounds offormula (I) wherein R₁ represents hydrogen, C₁₋₆alkyl, cyclopropyl,cyclohexyl, phenyl or phenyl substituted with two substituents eachindependently selected from halo; n is 1, 2 and 3; R₃ representshydrogen, cyano, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b) or C(═O)—R₈; R₄represents hydrogen, cyano, C₁₋₆alkyl optionally substituted withhydroxy, C(═O)—O—R₆ or C(═O)—NR_(7a)R_(7b); R₆ represents hydrogen,C₁₋₆alkyl or hydroxyC₁₋₆alkyl; R_(7a) represent hydrogen or C₁₋₆alkyl;and R_(7b) represents hydrogen, C₁₋₆alkyl or amino; or R_(7a) and R_(7b)taken together with the nitrogen to which they are attached formpiperidinyl; R₈ represents C₁₋₆alkyl and R₅ represents hydrogen.

A group of even more preferred compounds consists of those compounds offormula (I) wherein R₁ represents C₁₋₆alkyl; n is 2; each R₂independently represents halo; R₃ represents C(═O)—O—R₆; R₆ representsC₁₋₆alkyl; and R₅ represents hydrogen.

The most preferred compounds are compound No 37, compound No 39 andcompound No 46.

In general compounds of formula (I) wherein R₃ is other than hydrogen,said R₃ being represented by R₃ and R₄ is hydrogen, said compounds beingrepresented by formula (I-a), can be prepared by reacting anintermediate of formula (II) with HC(═O)—O—CH₃ (formic acid, methylester) in the presence of a suitable base, such as for example NaOCH₃ orNaOC(CH₃)₃, followed by treatment with a suitable acid, such as forexample hydrochloric acid (36%) and the like, and KSCN in the presenceof a suitable solvent, such as for example tetrahydrofuran.

When starting from a stereoisomeric pure intermediate of formula (II),the above reaction results in the preparation of a stereoisomeric purecompound of formula (I-a).

When R_(3′) in the intermediates of formula (II) represents CN, saidintermediates being represented by formula (II-a), the above reactionmay result in a compound of formula (I-a-1) and (I-a-2) as representedbelow.

Compounds of formula (I) wherein R₃ and R₄ are both other than hydrogen,said R₃ and R₄ substituents being represented by R₃ and R₄, and saidcompounds being represented by formula (I-b), can be prepared byreacting an intermediate of formula (II) with an intermediate of formula(III) in the presence of a suitable base, such as for example NaOCH₃ orNaOC(CH₃)₃, followed by treatment with a suitable acid, such as forexample hydrochloric acid (36%) and the like, and KSCN in the presenceof a suitable solvent, such as for example tetrahydrofuran.

The above reaction can also be performed by using R_(4′)—C(═O)—Cl orR_(4′)—C(═O)—O—C(CH₃)₃ instead of an intermediate of formula (III).

When R_(3′) and R_(4′) in the intermediates of formula (II) and (III)represent C(═O)—O—C₁₋₆alkyl, said intermediates being represented byformula (II-b) and (III-b), the above reaction may result in a compoundof formula (I-a-1) and (I-b-2) as represented below.

Compounds of formula (I) wherein R₃ represents R_(3′), said compoundsbeing represented by formula (I-c), can also be prepared by reacting anintermediate of formula (IV) with KSCN in the presence of a suitableacid, such as for example hydrochloric acid and the like, and a suitablesolvent, such as for example an alcohol, e.g. ethanol.

Compounds of formula (I) wherein both R₃ and R₄ are cyano and R₅ ishydrogen, said compounds being represented by formula (I-b-3), can beprepared by reacting an intermediate of formula (V) with Cl—C(═S)—Cl inthe presence of a suitable base, such as for exampleN,N-diethylethanamine, and a suitable solvent, such as for examplemethylene chloride.

Compounds of formula (I-a) wherein R₃ represents C(═O)—NR_(7a)R_(7b),said compounds being represented by formula (I-a-3), can be prepared byreacting an intermediate of formula (VI) wherein W₁ represents asuitable leaving group, such as for example a halogen, e.g. chloro andthe like, with an intermediate of formula (VII), such as for example NH₃(or acetic acid ammonium salt), pyrrolidine and the like, in thepresence of a suitable solvent, such as for example acetone,tetrahydrofuran, N,N-dimethylformamide and the like.

Compounds of formula (I-b-2) wherein R₄ represents C(═O)—NR_(7a)R_(7b),said compounds being represented by formula (I-b-4), can be prepared byreacting an intermediate of formula (XX) with an intermediate of formula(VII), such as for example NH₃ (or acetic acid ammonium salt)pyrrolidine and the like, in the presence of a suitable solvent, such asfor example acetone, tetrahydrofuran, N,N-dimethylformamide and thelike.

Compounds of formula (J-a) wherein R₃ represents C(═O)—O—R_(6′) whereinR_(6′) represents C₁₋₆alkyl or hydroxyC₁₋₆alkyl, said compounds beingrepresented by formula (I-a-4), can be prepared by reacting anintermediate of formula (VI) with an appropriate alcohol of formulaHO—R_(6′) in the presence of a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I-b-2) wherein R_(4′) represents CH₂—OH, saidcompounds being represented by formula (I-b-5), can be prepared byreacting an intermediate of formula (XX) with a suitable reducing agent,such as for example NaBH₄ in the presence of a suitable solvent, such asfor example tetrahydrofuran.

Compounds of formula (I) wherein R₃ is hydrogen and R₄ isC(═O)—O—C₁₋₆alkyl, said compounds being represented by formula (I-d),can be prepared by reacting an intermediate of formula (VIII) wherein W₂represents a suitable leaving group, such as for example C₁₋₆alkylthio,C₁₋₆alkyloxy or C₆H₅—CH₂-S—, with an alcoholate base, such as forexample NaOC₁₋₆alkyl, in the presence of the corresponding alcoholC₁₋₆alkyl-OH.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I-a), (I-b) or (I-d) wherein R₃ and/or R₄represent C(═O)—O—C₁₋₆alkyl, may be converted into a compound of formula(I-a), (I-b) or (I-d) wherein R_(3′) and/or R_(4′) represent CH₂—OH byreaction with a suitable reducing agent, such as for example LiHBEt₃ inthe presence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I-a), (I-b) or (I-d) wherein R₃ and/or R₄represent C(═O)—O—C₁₋₆alkyl, can also be converted into a compound offormula (I-a), (I-b) or (I-d) wherein R_(3′) and/or R_(4′) representC(═O)—OH by reaction with a suitable base, such as NaOH, in the presenceof a suitable solvent, such as for example H₂O, tetrahydrofuran or anappropriate alcohol, e.g. methanol and the like.

Compounds of formula (I-a), (I-b) or (I-d) wherein R₃ and/or R₄represent C(═O)—O—C₁₋₆alkyl, can also be converted into a compound offormula (I-a), (I-b) or (I-d) wherein R₃ and/or R₄ representC(═O)—NR_(7a)R_(7b), by reaction with the appropriate base of formulaNHR_(7a)R_(7b) in a suitable solvent, such as for example H₂O.

Compounds of formula (I-a), (I-b) or (I-d) wherein R_(3′) or R_(4′)represent cyano or C(═O)—O—C₁₋₆alkyl, can be converted into a compoundof formula (I-a), (I-b) or (I-d) wherein R_(3′) or R_(4′) representaminocarbonyl by reaction with NH₄OH.

Compounds of formula (I-a), (I-b) or (I-d) wherein R_(3′) or R_(4′)represent cyano, can be converted into a compound of formula (I-a),(I-b) or (I-d) wherein R_(3′) or R_(4′) represent C(═S)NR_(7a)R_(7b) byreaction with hydrogen sulfide in the presence ofN-ethyl-N-(1-methylethyl)-2-propanamine in a suitable solvent such aspyridine.

Compounds of formula (I-a), (I-b) or (I-d) wherein R_(3′) and/or R_(4′)represent C(═O)—NR_(7a)R_(7b) can be converted into compounds of formula(I-a), (I-b) or (I-d) wherein R₃ and/or R₄ represent C(═O)—C₁₋₆alkyl byreaction with chloroC₁₋₆alkyl-magnesium in a suitable solvent such astetrahydrofuran.

Compounds of formula (I-a), (I-b) or (I-d) wherein R_(3′) and/or R_(4′)represent C(═O)—C₁₋₆alkyl can be converted into compounds of formula(I-a), (I-b) or (I-d) wherein R_(3′) and/or R_(4′) representhydroxyC₁₋₆alkyl by reaction with a suitable reducing agent such asNaBH₄ in the presence of a suitable solvent such as methanol.

Compounds of formula (I-b) wherein R₃ and R₄ representC(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I-b)wherein R₃ and R₄ taken together form a bivalent radical of formula—C(═O)—NH—NH—C(═O)—, by reaction with hydrazine monohydrate in asuitable solvent, such as for example H₂O.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II) can be prepared by reacting anintermediate of formula (IX) with a H—C(═O)— introducing agent, such asfor example formic acid or n-butyl formate, in the presence of asuitable solvent, such as for example xylene.

The above reaction may result in stereochemically pure intermediates offormula (II) when starting from stereochemically pure intermediates offormula (IX).

Intermediates of formula (IX) can be prepared by reacting an intermedtaeof formula (X) with an intermediate of formula (XI) wherein W₃represents a suitable leaving group, such as for example a halogen, e.g.bromo and the like, in the presence of a suitable base, such as forexample N,N-diethylethanamine or N,N-diisopropylethanamine, and in thepresence of a suitable solvent, such as for exampleN,N-dimethylformamide.

The above reaction may result in stereochemically pure intermediates offormula (IX) when starting from stereochemically pure intermediates offormula (X).

Intermediates of formula (X) wherein R₅ represents hydrogen hereinreferred to as intermediates of formula (X-a) can be prepared byreducing an intermediate of formula (XII) in the presence of a suitablereducing agent, such as H₂, a suitable catalyst, such as for exampleRaney Nickel, a suitable catalyst poison, such as for example athiophene solution, and a suitable solvent, such as for example analcohol, e.g. methanol, in the presence of a suitable base, e.g. NH₃.Alternatively, said reaction can also be performed in the presence of Znand a suitable acid, such as for example acetic acid.

Intermediates of formula (XII) can be prepared by reacting anintermediate of formula (XIII) with NH₂—OH in the presence of a suitablebase, such as for example NaOC(═O)CH₃, and a suitable solvent, such asfor example an alcohol, e.g. methanol.

Alternatively to the methods described above, intermediates of formula(X) can also be prepared from an azido derivative of formula (XIV) byreaction with triphenylphosphine in the presence of a suitable solvent,such as for example tetrahydrofuran and H₂O.

Intermediates of formula (X) can also be prepared from an intermediateof formula (XIV) by catalytic hydrogenation in the presence of H₂, asuitable catalyst, such as for example Pt/C (5%), and a suitablesolvent, such as for example an alcohol, e.g. methanol.

Intermediates of formula (XIV) can be prepared by reacting anintermediate of formula (XV) with phosphorazidic acid diphenylester inthe presence of 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine and asuitable solvent, such as for example toluene.

Intermediates of formula (XV) wherein R₁ is C₁₋₆alkyl and wherein R₅ ishydrogen, said intermediates being represented by formula (XV-a), can beprepared by reacting an intermediate of formula (XIII) wherein R₁represents hydrogen, said intermediates being represented by formula(XIII-a), with (C₁₋₆alkyl)₂Zn, N,N′-1,2-cyclohexanediylbis[1,1,1-trifluoro]methanesulfonamide, Ti(i-PrO)₄ and toluene.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (X) with an intermediate of formula (XVI)wherein W₄ represents a suitable leaving group, such as for example ahalogen, e.g. chloro and the like, in the presence of a suitable base,such as for example N,N-diethylethanamine or N,N-diisopropylethylamine,and a suitable solvent, such as for example N,N-dimethylformamide ortetrahydrofuran.

Intermediates of formula (V) can be prepared by reducing an intermediateof formula (XVII) in the presence of a suitable reducing agent, such asfor example NaBH₄, and a suitable solvent, such as for exampletetrahydrofuran and an alcohol, e.g. methanol.

Intermediates of formula (XVII) can be prepared by reacting anintermediate of formula (XIII) with 2,3-diamino-2-butenedinitrile in thepresence of P₂O₅ (phosphorus anhydride) and a suitable solvent.

Intermediates of formula (VI) wherein W₁ represents chloro, saidintermediates being represented by formula (VI-a), can be prepared byreacting a compound of formula (I-a) wherein R_(3′) represents C(═O)—OH,said compound being represented by formula (I-a-5), with SOCl₂.

Intermediates of formula (XX) wherein W₁ represents chloro, saidintermediates being represented by formula (XX-a), can be prepared byreacting a compound of formula (I-b-2) with SOCl₂.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (XVIII) with an intermediate of formula (XIX) inthe presence of a suitable solvent, such as for example toluene.

Intermediates of formula (XVIII) can be prepared by reacting anintermediate of formula (X) with 1,1-dimethoxy-N,N-dimethylmethanamine.

The compounds of formula (I) show CCR2 receptor antagonistic properties.

The C—C chemokine receptor 2 (CCR2) and its ligand monocytechemoattractant (chemotactic) protein (MCP-1; in new chemokinenomenclature also called CCL2) are recognized to be implicated in bothacute and chronic inflammatory processes.

Chemokines (contraction of “chemotactic cytokines”) are most importantregulators of leukocyte trafficking. This biological role is exerted byinteracting—on target cells—with seven-transmembrane-domain receptorsthat are coupled to heterodimeric G proteins. Chemokines are mainlygrouped into 2 families (C—C or C—X—C family) dependent on the presenceof an amino acid (represented by X) between the two conserved cysteineresidues (represented by C) near the amino terminus. In general,chemokines from the C—C family attract monocytes, macrophages, T cellsand NK cells.

A chemokine, which acts through the CCR2 receptor, is MCP-1 as indicatedabove. Therefore, the CCR2 receptor is also known as the Chemoattractantprotein-1 receptor. MCP-2 and MCP-3 may also act, at least in part,through this receptor.

It is recognized that the CCR2 receptor and MCP-1 play a role in thepathophysiology of various inflammatory diseases. Therefore, CCR2receptor antagonists, which block the CCR2 receptor, have potential aspharmaceutical agents to combat inflammatory conditions such asarthritis, osteoarthritis, rheumatoid arthritis, glomerular nephritides,lung fibrosis, sarcoidosis, vasculitis, hepatitis, inflammatoryconditions of the brain such as Alzheimer's disease, restenosis,alveolitis, asthma, atherosclerosis, psoriasis, delayed-typehypersensitivity reactions of the skin, inflammatory bowel disease,multiple sclerosis, chronic obstructive pulmonary disease (COPD),uveitis. CCR2 receptor antagonists may also be useful to treatautoimmune diseases such as diabetes or transplant rejection, stroke,reperfusion injury, ischemia and myocardial infraction.

The compounds of the present invention may also be used to inhibit theentry of Human Immunodeficiency Virus (HIV) into monocytes andlymphocytes, thereby having a therapeutic role in the treatment of AIDS(Acquired Immunodeficiency Syndrome).

The CCR2 receptor exists in two isoforms, namely the CCR2A and the CCR2Breceptor.

Due to their CCR2 receptor antagonistic activity, in particular theirCCR2B receptor antagonistic activity, the compounds of formula (I),their N-oxides, pharmaceutically acceptable addition salts, quaternaryamines and stereochemically isomeric forms are useful in the treatmentor prevention of diseases or conditions mediated through the activationof the CCR2 receptor, in particular the CCR2B receptor. Diseases orconditions related to an activation of the CCR2 receptor comprisearthritis, osteoarthritis, rheumatoid arthritis, glomerular nephritides,lung fibrosis, sarcoidosis, vasculitis, hepatitis, inflammatoryconditions of the brain such as Alzheimer's disease, restenosis,alveolitis, asthma, atherosclerosis, psoriasis, delayed-typehypersensitivity reactions of the skin, inflammatory bowel disease,multiple sclerosis, chronic obstructive pulmonary disease (COPD),uveitis, auto-immune diseases (diabetes, transplant rejection), stroke,reperfusion injury, ischemia, myocardial infraction. In particular, thecompounds of formula (I) are useful in the treatment or prevention ofinflammatory diseases and autoimmune diseases, especially rheumatoidarthritis, atherosclerosis, multiple sclerosis, inflammatory boweldisease and chronic obstructive pulmonary disease (COPD).

In view of the above-described pharmacological properties, the compoundsof formula (I), their N-oxides, pharmaceutically acceptable additionsalts, quaternary amines and stereochemically isomeric forms, may beused as a medicine. In particular, the present compounds can be used forthe manufacture of a medicament for treating or preventing diseasesmediated through activation of the CCR2 receptor, in particular theCCR2B receptor. More in particular, the compounds of the invention canbe used for the manufacture of a medicament for treating or preventinginflammatory diseases, especially rheumatoid arthritis, atherosclerosis,multiple sclerosis, inflammatory bowel disease and chronic obstructivepulmonary disease (COPD).

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from diseases mediated through activation of the CCR2receptor, in particular mediated through the CCR2B receptor. Saidmethods comprise the administration of an effective amount of a compoundof formula (I), a N-oxide form, a pharmaceutically acceptable additionsalt, a quaternary amine or a possible stereoisomeric form thereof, towarm-blooded animals, including humans.

The blockade of the CCR2 receptor by the present compounds of formula(I) inhibits the normal function of MCP-1. Therefore, the presentcompounds can also be described as MCP-1 inhibitors and hence can beused to prevent or treat diseases mediated through MCP-1.

The present invention also provides compositions for preventing ortreating diseases mediated through activation of the CCR2 receptor, inparticular the CCR2B receptor. Said compositions comprise atherapeutically effective amount of a compound of formula (I) and apharmaceutically acceptable carrier or diluent.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs. To prepare the pharmaceuticalcompositions of this invention, an effective amount of the particularcompound, optionally in addition salt form, as the active ingredient iscombined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs,emulsions and solutions; or solid carriers such as starches, sugars,kaolin, diluents, lubricants, binders, disintegrating agents and thelike in the case of powders, pills, capsules, and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit forms, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations, whichare intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions.

These compositions may be administered in various ways, e.g., as atransdermal patch, as a spot-on, as an ointment.

The compounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

The compounds of the present invention may also be topicallyadministered in the form of drops, in particular eye drops. Said eyedrops may be in the form of a solution or a suspension. Any systemdeveloped for the delivery of solutions or suspensions as eye drops aresuitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

The compounds of formula (I) may also be used in combination with otherconventional anti-inflammatory or immunosuppressive agents, such assteroids, cyclooxygenase-2 inhibitors, non-steroidal-anti-inflammatorydrugs, TNF-α antibodies, such as for example acetyl salicylic acid,bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolactrometamol, tolmetine, ibuprofen, naproxen, naproxen sodium, tiaprofenacid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate,indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol,piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasonedipropionate, betamethasone, beclamethasone, budesonide, fluticasone,mometasone, dexamethasone, hydrocortisone, methylprednisolone,prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib,valdecoxib, infliximab, leflunomide, etanercept, CPH 82, methotrexate,sulfasalazine, antilymphocytory immunoglobulines, antithymocytoryimmunoglobulines, azathioprine, cyclosporine, tacrolimus substances,ascomycin, rapamycin, muromonab-CD3.

Thus, the present invention also relates to the combination of acompound of formula (I) and another anti-inflammatory orimmunosuppressive agent. Said combination may be used as a medicine. Thepresent invention also relates to a product containing (a) a compound offormula (I), and (b) another anti-inflammatory or immunosuppressivecompound, as a combined preparation for simultaneous, separate orsequential use in the treatment of diseases mediated through activationof the CCR2 receptor, in particular mediated through the CCR2B receptor.The different drugs in such products may be combined in a singlepreparation together with pharmaceutically acceptable carriers.Alternatively, such products may comprise, for example, a kit comprisinga container with a suitable composition containing a compound of formula(I) and another container with a composition containing anotheranti-inflammatory or immunosuppressive compound. Such a product may havethe advantage that a physician can select on the basis of the diagnosisof the patient to be treated the appropriate amounts of each componentand the sequence and timing of the administration thereof.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART

Hereinafter, “DIPE” is defined as diisopropyl ether, “DMA” is defined asN,N-dimethylacetamide, “DMF” is defined as N,N-dimethylformamide and“THF” is defined as tetrahydrofuran, ‘SOCl₂’ means thionyl chloride,‘EtOH’ means ethanol, ‘EtOAc’ means ethyl acetate, ‘Et₂O’ means diethylether, ‘Ti(iPrO)₄’ means tetrakis(isopropanolato)titanium, ‘P(Ph)₃’means triphenyl-phosphine, and ‘Et₃N’ means triethylamine.

A. Preparation of the Intermediates Example A1 a. Preparation ofIntermediate 1

1-[4-fluoro-3-(trifluoromethyl)phenyl]-1-propanone (0.0441 mol) inmethanol p.a. (200 ml) was stirred on an ice bath. NaOAc (0.0883 mol)was added, then hydroxylamine.hydrochloride (0.0574 mol) was added. Thereaction mixture was stirred at 0° C. for 90 minutes and at roomtemperature for 18 hours. The solvent was evaporated, the residue wasstirred in CH₂Cl₂ and washed with a 10% aq. NaHCO₃ solution. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated, then co-evaporated with toluene (2×). Yield: intermediate 1.

b. Preparation of Intermediate 2

A solution of intermediate 1 (0.044 mol) in CH₃OH/NH₃ (7N) (250 ml) washydrogenated at 14° C. with Raney Nickel (cat. quant.) as a catalyst inthe presence of thiophene solution (1 ml). After uptake of H₂ (2 equiv.,gas), the catalyst was filtered off and washed with CH₃OH. The filtratewas evaporated, then co-evaporated 2 times with toluene. The residue wasdissolved in 2-propanol (75 ml) and converted into the hydrochloric acidsalt (1:1) with HCl/2-propanol (25 ml, 6N). The solvent was evaporatedand the precipitate (salt) was stirred in DIPE (100 ml), filtered off,washed, then dried (vac., 50° C.). Yield: 9.67 g of intermediate 2(85.3%).

c. Preparation of Intermediate 3

A solution of intermediate 2 (0.373 mol) and 2-bromoacetic acid methylester (0.045 mol) in DMF (p.a., dried on molecular sieves) (100 ml) wasstirred under N₂-flow, then Et₃N (0.112 mol) was added and the reactionmixture was stirred for 20 hours at room temperature. Extra2-bromoacetic acid methyl ester (1.25 ml) was added and the mixture wasstirred for 68 hours at room temperature. The resulting precipitate wasfiltered off and washed with DMF. The precipitate/DMF mixture wasfiltered and the filtrate was treated with Et₂O (600 ml) and washed withH₂O (3 times 300 ml). The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated, then co-evaporated 2 times withtoluene. Yield: 10.94 g of intermediate 3.

d. Preparation of Intermediate 4

A solution of intermediate 3 (0.0372 mol) in formic acid (3.75 ml) andxylene, p.a. (110 ml) was stirred and refluxed for 6 hours, then thereaction mixture was stirred overnight, washed 2 times with H₂O, with asaturated aq. NaHCO₃ solution and with brine. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated.Yield: 11.3 g of intermediate 4.

Example A2 a. Preparation of Intermediate 5

A mixture of cyclopropyl(3,4-dichlorophenyl)methanone oxime (0.16 mol)and Zn (75 g) in acetic acid (750 ml) was stirred at room temperaturefor 18 hours, then the reaction mixture was filtered over celite and thefiltrate was evaporated. The residue was stirred in H₂O and dissolved,then the solution was treated with Na₂CO₃ and extracted with CH₂Cl₂. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was dissolved in 2-propanol and converted intothe hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitatewas filtered off, washed with DIPE, then dried. Yield: 26.8 g ofintermediate 5.

b. Preparation of Intermediate 6 and 7

A mixture of (3,4-dichlorophenyl)phenylmethanone oxime (0.132 mol) andZn (70 g) in acetic acid (700 ml) was stirred at room temperature for 18hours, then the reaction mixture was filtered over decalite (to removeZn) and the filtrate was evaporated. The residue was dissolved in H₂O(±150 ml) and converted into the acetic acid salt (1:1). The precipitatewas filtered off and dried. Yield: 31 g of intermediate 6. The filtratewas treated with Na₂CO₃ and extracted with CH₂Cl₂. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas dissolved in 2-propanol and converted into the hydrochloric acidsalt (1:1) with HCl/2-propanol. The precipitate was filtered off anddried. Yield: 5 g of intermediate 7.

Example A3 Preparation of Intermediate 8

A mixture of 3,4-dichloro-α-ethylbenzenemethanamine (0.0098 mol) and2-chloro-3-oxo-butanoic acid methyl ester (0.0166 mol) in Et₃N (5 ml)was stirred in DMF (50 ml) at room temperature for 18 hours, then thereaction mixture was poured out into H₂O (200 ml) and extracted withdiethyl ether (150 ml). The ether layer was washed 3 times with H₂O (200ml), dried (MgSO₄), filtered and the solvent was evaporated. Yield:intermediate 8.

Example A4 a. Preparation of Intermediate 9

A mixture ofN,N′-1,2-cyclohexanediylbis[1,1,1-trifluoromethanesulfonamide](1R-trans) (0.189 g) and Ti(iPrO)₄ (0.030 mol) in toluene was degassed,placed under Ar flow, then stirred for 20 minutes at 40° C. The mixturewas cooled to −78° C. and Et₂Zn (0.03 mol) was added dropwise. After 20minutes, 3,4-dichlorobenzaldehyde (0.0250 mol) in toluene was addeddropwise and the reaction mixture was allowed to warm up to 0° C. Themixture was stirred overnight at room temperature, then quenched with 2N HCl. This mixture was extracted with CH₂Cl₂. The separated organiclayer was washed, dried, filtered and the solvent evaporated. Yield: 5.1g of intermediate 9 (S-isomer).

b. Preparation of Intermediate 10

A mixture of intermediate 9 (0.025 mol) and phosphorazidic acid diphenylester (0.030 mol) in toluene (50 ml) was stirred at 0° C.2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a]azepine (0.030 mol) was addedand the reaction mixture was stirred for 2 hours at 0° C., thenovernight at room temperature. The reaction mixture was diluted withwater and toluene. The organic layer was separated, washed once withwater, once with 5% HCl, and the solvent was evaporated. Yield:intermediate 10 (R-isomer).

c. Preparation of Intermediate 11

A mixture of intermediate 10 (0.025 mol), P(Ph)₃ (0.027 mol) in THF (70ml) and H₂O (20 ml) was stirred overnight at room temperature. Thesolvent was evaporated. The residue was treated with 10% HCl. The acidiclayer was washed with DIPE, then alkalized, followed by an extractionwith CH₂Cl₂. The separated organic layer was dried, filtered and thesolvent evaporated. The residue was purified by column chromatographyover silica gel. The product fractions were collected and the solventwas evaporated. Yield: 1.1 g of intermediate 11 (R-isomer).

d. Preparation of Intermediate 12

A solution of intermediate 11 (0.0116 mol) in Et₃N (0.013 mol) and DMFp.a. (20 ml) was stirred on an ice bath. A solution ofchloroacetonitrile (0.0128 mol) in DMF p.a. (2.5 ml) was added dropwise.The reaction mixture was stirred at room temperature for 6 hours. Threemore portions of chloroacetonitrile were added over the next 68 hoursuntil the reaction was complete. The precipitate was filtered off. Thefiltrate was poured out into Et₂O (200 ml) and washed with H₂O/NaHCO₃(10%; 100 ml) and H₂O (2×). The separated organic layer was dried(MgSO₄), filtered and the solvent was evaporated and coevaporated withtoluene. The residue was purified over silica gel (eluent: CH₂Cl₂/MeOH99:1). The desired fractions were collected and the solvent wasevaporated and coevaporated with toluene. Yield: 2.3 g of intermediate12 (81.6%).

e. Preparation of Intermediate 13

A mixture of intermediate 12 (0.00946 mol) and n-butyl-formate (15 ml)was stirred and refluxed for 4 days. The solvent was evaporated, thenco-evaporated with toluene. Yield: 2.68 g of intermediate 13.

Example A5 Preparation of Intermediate 14

Compound 22 (prepared according B14) (0.0107 mol) was treated with SOCl₂(20 ml) and the reaction mixture was stirred at 60° C. for 2 hours.Excess of SOCl₂ was evaporated, then the residue was co-evaporated 2times with toluene (2×30 ml). Yield: intermediate 14.

Example A6 a. Preparation of Intermediate 15

A mixture of 1-(3,4-dichlorophenyl)ethanone (0.0278 mol) and2,3-diamino-2-butenedinitrile (0.0278 mol) was stirred in EtOH (p.a) (75ml) under N₂-atm., then P₂O₅ (phosphorus anhydride) (0.0106 mol) wasadded portionwise, the reaction mixture was stirred for 2 hours andstood overnight. The resulting precipitate was filtered off, washed withEtOH, with DIPE and with H₂O, then dried. Yield: 2.85 g of intermediate15 (36.7%)

b. Preparation of Intermediate 16

NaBH₄ (0.013 mol) was added portionwise to a solution of intermediate 15(0.01 mol) in CH₃OH (30 ml) and THF, p.a. (40 ml), then the reactionmixture was stirred for 2 hours. The mixture was diluted with H₂O (275ml) and extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue wasstirred in CH₂Cl₂/CH₃OH (99.5/0.5), then the precipitate was filteredoff, washed with CH₂Cl₂, with DIPE and dried (vac., 45° C.). Yield: 0.86g of intermediate 16.

Example A7 a. Preparation of Intermediate 17

A mixture of 3,4-dichloro-α-ethylbenzenemethanamine (0.04 mol) in1,1-dimethoxy-N,N-dimethylmethanamine (80 ml) was stirred and refluxedfor 3 hours, then the solvent was evaporated and co-evaporated 2 timeswith toluene. Yield: intermediate 17.

b. Preparation of Intermediate 18

A solution of intermediate 17 (0.035 mol) and2-[(phenylmethyl)thio]-5(4H)-thiazolone (0.035 mol) in toluene, p.a.(200 ml) was stirred at 60° C. for 2.5 hours, stirred overnight at roomtemperature, then stirred at 60° C. for 2 hours. The solvent wasevaporated and the residue was purified by filtration over silica gel(eluent: CH₂Cl₂/Hexane 50/50). The product fractions were collected andthe solvent was evaporated, then co-evaporated with CH₃OH. Yield: 5.9 gof intermediate 18.

Example A8 a. Preparation of Intermediate 19

A mixture of intermediate 11 (prepared according to A4.c) (0.0054 mol),bromoacetic acid methyl ester (0.0055 mol) and Et₃N (0.006 mol) in DMF(q.s.) was stirred overnight at room temperature, then poured out intowater. This mixture was extracted with CH₂Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated. Yield: 1.3 g ofintermediate 19 (R-isomer).

b. Preparation of Intermediate 20

A mixture of intermediate 19 (0.0054 mol) in formic acid (3 ml) andxylene (50 ml) was stirred and refluxed for 20 hours. The reactionmixture was cooled, washed with water, dried, filtered and the solventevaporated. Yield: 1.3 g of intermediate 20 (R-isomer).

Example A9 a. Preparation of Intermediate 21

A solution of Na₂CO₃ (part of 0.52 mol) in water (150 ml) was added to astirring mixture of 1-(3,4-dichlorophenyl)-1-propanone (0.345 mol) inethanol p.a. (150 ml), then the remainder of Na₂CO₃ was added andhydroxylamine hydrochloride (0.345 mol) was added portionwise whilestirring vigorously. The reaction mixture was heated to refluxtemperature and extra water (75 ml) was added (to improve solubility ofinorganic material), then the resulting mixture was stirred and refluxedfor 6 hours. Extra hydroxylamine hydrochloride (2.4 g) was added and themixture was refluxed further for 18 hours. Again extra hydroxylaminehydrochloride (3 g) was added; the reaction mixture was refluxed for 24hours and stirred for 2 days at room temperature. The solids werefiltered off, washed with ethanol/water (1/1) and dried (vacuum, streamof air) at 56° C. Yield: 71.8 g (95.4%) of intermediate 21.

b. Preparation of Intermediate 22

A mixture of intermediate 21 (0.3 mol) in CH₃OH/NH₃ 7N (500 ml) washydrogenated at 14° C. with raney nickel (cat. quant.) as a catalyst inthe presence of thiophene solution (6 ml). After uptake of H₂ (2equiv.), the catalyst was filtered off and the filtrate was evaporated,then co-evaporated 2 times with toluene. The residue was stirred inboiling 2-propanol (250 ml) and the mixture was filtered off hot. Thefiltrate was allowed to reach room temperature and HCl/2-propanol (6N,150 ml) was added slowly while stirring vigorously. The solvent wasevaporated and the residue was stirred in DIPE, then filtered off,washed and dried (vacuum) at 60° C. Yield: 53 g (73.4%) of intermediate22, isolated as a hydrochloric acid salt.

c. Preparation of Intermediate 23

A solution of intermediate 22 (0.0748 mol) and chloro-acetic acid,methyl ester (0.08 mol) in DMF, p.a. dried on molecular sieves (150 ml)was stirred at room temperature under N₂ and Et₃N (0.224 mol) was slowlyadded, then the reaction mixture was stirred for 20 hours at roomtemperature and extra chloro-acetic acid, methyl ester (3.3 ml) wasadded. The mixture was stirred for another 20 hours at room temperatureand again extra chloro-acetic acid, methyl ester (2 ml) was added. Theresulting mixture was stirred for 24 hours and then the solids werefiltered off and washed with DMF. Et₂O (800 ml) was added and themixture was washed 3 times with water (500 ml). The organic layer wasseparated, dried (MgSO₄), filtered off and the solvent was evaporated,then co-evaporated with toluene. The residual oil (23.4 g) was filteredover silica gel (eluent: CH₂Cl₂/CH₃OH 99/1). The product fractions werecollected and the solvent was evaporated, finally co-evaporated withtoluene. Yield: 20.6 g (99.7%) of intermediate 23.

d. Preparation of Intermediate 24

A solution of formic acid (7.5 ml) and intermediate 23 (0.0746 mol) inxylene p.a. (225 ml) (biphasic) was stirred and refluxed for 4 hours andthen the reaction mixture was allowed to reach room temperature. Themixture was washed 2 times with water (2×200 ml), with a saturatedaqueous NaHCO₃ solution (200 ml) and with a saturated NaCl solution (200ml), then the separated organic layer was dried (MgSO₄) and filteredoff. Finally, the solvent was evaporated. Yield: 21.3 g (93.9%) ofintermediate 24.

Example A10 a. Preparation of Intermediate 25

A mixture ofN,N′-(1S,2S)-1,2-cyclohexanediylbis[1,1,1-trifluoromethanesulfonamide(0.060 g) and Ti(iPrO)₄ (8.5 g) in toluene was degassed, placed under Arflow, then stirred for 20 minutes at 40° C. The mixture was cooled to−78° C. and diethylzinc (q.s.) was added dropwise. After 20 minutes,3,4-dichloro-benzaldehyde (0.025 mol) in toluene (q.s.) was addeddropwise and the reaction mixture was allowed to warm up to 0° C., thenwas stirred overnight at room temperature, quenched with 2 N HCl andextracted with CH₂Cl₂. The separated organic layer was washed, dried,filtered and the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The productfractions were collected and the solvent was evaporated. Yield: 5 g ofintermediate 25 (R).

b. Preparation of Intermediate 26

A mixture of intermediate 25 (0.127 mol) and phosphorazidic acid,diphenyl ester (0.153 mol) in toluene (q.s.) was stirred at 0° C.2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.153 mol) was addeddropwise and the reaction mixture was stirred for 1 hour at 0° C., thenfor 2 hours at room temperature, then for 3 hours at 50° C. The reactionmixture was cooled, washed with water, with 0.5 M HCl, with water,dried, filtered and the solvent evaporated. The residue was purified byflash column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH99.5/0.5). The product fractions were collected and the solvent wasevaporated. Yield: 23.5 g of intermediate 26, S-(−).

c. Preparation of Intermediate 27

A mixture of intermediate 26 (0.122 mol) in methanol (q.s.) washydrogenated at 50° C. with Pt/C₅% (5 g) as a catalyst. After uptake ofH₂, the catalyst was filtered off and the filtrate was evaporated.Yield: intermediate 27.

d. Preparation of Intermediate 28

A mixture of intermediate 27 (0.050 mol), methyl bromoacetate (0.060mol) and Et₃N (15 ml) in DMF (100 ml) was stirred overnight at roomtemperature. More methyl bromoacetate was added, and the reactionmixture was stirred overnight at room temperature, then poured out intowater. This mixture was extracted with CH₂Cl₂. The separated organiclayer was dried, filtered and the solvent evaporated. Yield: 12 g ofintermediate 28.

e. Preparation of Intermediate 29

A mixture of intermediate 28 (0.05 mol) in formic acid (100 ml) andxylene (150 ml) was stirred and refluxed for 48 hours. The reactionmixture was cooled, poured out into water, then extracted with toluene.The separated organic layer was washed with water, treated with NaHCO₃,dried, filtered and the solvent evaporated. Yield: 13.2 g ofintermediate 29.

Example A11 a. Preparation of Intermediate 30

A mixture of 3,4-dichloro-α,α-dimethyl-benzenemethanamine (0.032 mol) inmethyl bromoacetate (6 ml), DMF (50 ml) and Et₃N (15 ml) was reactedovernight at room temperature and after partial conversion, the reactionmixture was heated to 45° C. for 6 hours. The mixture was filtered,diluted with CH₂Cl₂ and washed 5 times with water, then dried and thesolvent was evaporated. Yield: intermediate 30.

b. Preparation of Intermediate 31

A mixture of intermediate 30 (residue) in formic acid (50 ml) and xylene(50 ml) was stirred and refluxed for 18 hours, then the reaction mixturewas cooled and partitioned between water and toluene. The organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The product fractions werecollected and the solvent was evaporated. The impure residue waspurified by high-performance liquid chromatography. The pure productfractions were collected and the solvent was evaporated. Yield: 2.1 g ofintermediate 31.

B. Preparation of the Final Compounds of Formula (I) Example B1 a.Preparation of Compound 1

A solution of intermediate 4 (prepared according to A1.d) (0.0177 mol),formic acid methyl ester (0.05 mol) and THF (p.a., dried on molecularsieves) (30 ml) was stirred under N₂-flow, then NaOMe (prepared in situ;see note below) (0.0185 mol) was added and the reaction mixture wasstirred at room temperature for 20 hours. The solvent was evaporated,the residue was stirred in H₂O (40 ml) and washed 2 times with Et₂O—MeOH (35 ml), then HCl (36%, p.a.) (4.2 ml) was added to the separatedaqueous layer. KSCN (0.03 mol) was added and the resulting solution wasstirred at 50° C. for 6 hours, then for 20 hours at room temperature, at80° C. for 3 hours and finally stirred overnight at room temperature.The resulting precipitate was filtered off, washed with CH₃OH/H₂O (1/2)and dried (vac., 60° C.). Yield: 4.25 g of compound 1.

Note: NaOMe was generated in situ with NaH (0.74 g, 60% in mineral oil)and MeOH (0.74 ml) in THF (15 ml; p.a., dry).

b. Preparation of Compound 2

A mixture of

(prepared according to A1.d) (0.02 mol) and formic acid methyl ester(0.06 mol) in THF (100 ml) was stirred at room temperature, then2-methyl-2-propanol sodium salt (0.025 mol) was added and the reactionmixture was stirred for 3 hours at room temperature. The solvent wasevaporated, the residue was stirred in H₂O (±100 ml) for 15 minutes andwashed with Et₂O. The aqueous layer was separated, then HCl (conc.)(0.06 mol) was added. CH₃OH (±100 ml) was added, then KSCN (0.03 mol)was added and the reaction mixture was stirred for 18 hours at 60° C.The mixture was stirred at room temperature for 2 hours, then stirred inhexane. The precipitate was filtered off and dried. Yield: 6.4 g ofcompound 2.

Example B2 a. Preparation of Compound 3

A solution of intermediate 4 (prepared according to A1.d) (0.0174 mol),ethanedioic acid dimethyl ester (0.03 mol) and THF (p.a., dried onmolecular sieves) (30 ml) was stirred, then NaOMe (prepared in situ; seenote below) (0.0185 mol) was added and the reaction mixture was stirredat room temperature for 18 hours. The solvent was evaporated, theresidue was stirred in H₂O (50 ml) and washed with Et₂O (2 times). MeOH(35 ml), then HCl (36%, p.a.) (4.2 ml) was added to the separatedaqueous layer. KSCN (0.03 mol) was added and the resulting solution wasstirred at 50° C. for 18 hours. The mixture was allowed to reach roomtemperature, then extra H₂O was added and the mixture was extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98.5/1.5). Thepurest product fractions were collected and the solvent was evaporated.The residue was further purified by flash column chromatography on FlashTubes (eluent: CH₂Cl₂/THF 95/5). The product fractions were collectedand the solvent was evaporated, then the residue was filtered off anddried. Yield: 0.0186 g of compound 3.

Note: NaOMe was generated in situ with NaH (0.74 g, 60% in mineral oil)and MeOH (0.74 ml) in THF (15 ml; p.a., dry).

b. Preparation of Compound 4

A mixture of

(prepared according to A1.d) (0.02 mol) and ethanedioic acid dimethylester (0.04 mol) in THF (100 ml) was stirred at room temperature, then2-methyl-2-propanol sodium salt (0.025 mol) was added in one portion andthe reaction mixture was stirred for 18 hours at 60° C. Extra2-methyl-2-propanol sodium salt (0.025 mol) was added portionwise at 60°C. and the reaction mixture was stirred overnight at 60° C. Again, extra2-methyl-2-propanol sodium salt (0.005 mol) was added at 60° C. and themixture was stirred further at 60° C. for 3 hours. The solvent wasevaporated, the residue was stirred in H₂O and washed with Et₂O. Theaqueous layer was separated, then HCl (conc.) (5 ml) was added. A solidwas precipitated and CH₃OH was added (until the solution was clear),then KSCN (0.03 mol) was added and the reaction mixture was stirred for20 hours at 60° C. The organic solvent (CH₃OH) was evaporated and theaqueous concentrate was extracted with CH₂Cl₂. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residuewas purified by filtration over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2).The product fractions were collected and the solvent was evaporated. Theresidue was crystallised from DIPE, filtered off and dried. Yield: 2 gof compound 4.

c. Preparation of Compound 5

Intermediate 13 (prepared according to A4.e) (0.0136 mol) was added to amixture of NaH (60%) (0.6 g) in THF (50 ml), then ethanedioic aciddimethyl ester (0.0152 mol) was added and the reaction mixture wasstirred for 5 hours at room temperature. The mixture was poured out intoH₂O and the aqueous layer was extracted with CH₂Cl₂. The organic layerwas separated and acidified, then the aqueous layer was extracted withCH₂Cl₂. The organic layer was filtered and the solvent was evaporated.The residue was treated with CH₃OH (20 ml), with H₂O (20 ml) and withHCl (5 ml, 1N). A mixture of KSCN (1 g) in H₂O (10 ml) was added and thereaction mixture was stirred at 60° C. for 18 hours. The resultingprecipitate was filtered off and purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 90/10). The product fractions werecollected and the solvent was evaporated. Yield: 0.700 g of compound 5.

d. Preparation of Compounds 37 and 68

A solution of

(0.0618 mol) and ethanedioic acid dimethyl ester (0.11 mol) in THF(p.a., dried on molecular sieves) (100 ml) was stirred under N₂-atm.,then 2-methyl-2-propanol sodium salt (0.066 mol) was added and thereaction mixture was stirred at room temperature for 18 hours andanother for 24 hours. Finally the mixture was stirred at 60° C. for 4hours. Extra 2-methyl-2-propanol sodium salt (4 g) and extra ethanedioicacid dimethyl ester (6 g) were added and the reaction mixture wasstirred over the weekend at room temperature. The solvent wasevaporated, the residue was dissolved in H₂O (250 ml) and washed 2 timeswith Et₂O. The aqueous layer was separated and CH₃OH (200 ml), KSCN (10g) and HCl (36%, p.a.) (q.s.) were added, then the mixture was stirredfor 18 hours at 60° C. The solvent was partly evaporated and theconcentrate was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The residue (5g) was purified by filtration over silica gel (eluent: CH₂Cl₂/CH₃OH99/1). The product fractions were collected and the solvent wasevaporated. The residue was triturated under Hexane, filtered off,washed, then dried (vac., 50° C.) Yield: 5.2 g of compound 37. Thefractions containing a side-product were combined and the solvent wasevaporated, then co-evaporated with Hexane/DIPE. The residue was stirredin Et₂O/Hexane and the resulting precipitate was filtered off, washedwith hexane, then dried (vac., 50° C.). Yield: 0.28 g of compound 68.

Example B3 Preparation of Compound 6

A mixture of intermediate 8 (prepared according to A3) (0.0079 mol) andKSCN (0.031 mol) in HCl (1N) (5 ml) was stirred in EtOH (50 ml) at 80°C. for 4 hours. The reaction mixture was poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified byreversed phase chromatography. The product fractions were collected andthe solvent was evaporated to fifty percent less of the initial volume.The residue was extracted with CH₂Cl₂, then the organic layer wasseparated, dried, filtered and the solvent was evaporated. Yield: 0.3 gof compound 6.

Example B4 Preparation of Compounds 7 and 8

A solution of intermediate 13 (prepared according to A4.e) (0.0094 mol),formic acid methyl ester (0.027 mol) and THF (p.a. dried on molecularsieves) (15 ml) was stirred under N₂ flow. NaOMe (prepared in situ; seenote) (0.01 mol) was added and the reaction mixture was stirred at roomtemperature for 20 hours. The solvent was evaporated. The residue wasdissolved in H₂O (20 ml) and washed with Et₂O (2×20 ml). MeOH (15 ml)was added to the separated aqueous layer. Then HCl (36%, pa.) (2.25 ml)was added. KSCN (1.52 g) was added and the reaction mixture was stirredat 50° C. for 5 hours, at room temperature for 16 hours and refluxed for5 hours. Then it was allowed to cool to room temperature. The liquidlayer was decanted. The oily layer was dissolved in CH₂Cl₂/MeOH (95:5)and washed with H₂O. The separated organic layer was dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified byflash column chromatography over silica gel (eluent: CH₂Cl₂/MeOHgradient). The desired fractions were collected and the solvent wasevaporated. Yield Fraction 1: 0.065 g of compound 7 and yield Fraction2: 0.063 g of compound 8

Note: NaOMe was generated in situ with NaH (0.4 g, 60% in mineral oil)and MeOH (0.4 ml) in THF (10 ml; p.a., dry).

Example B5 a. Preparation of Compound 9

A mixture of intermediate 14 (prepared according to A5) (0.00158 mol)and acetic acid ammonium salt (0.00649 mol) was stirred in acetone(q.s.) for 2 hours at room temperature, then the solvent was evaporated.The residue was purified by reversed phase chromatography. The productfractions were collected and the aqueous layer was evaporated to fiftypercent less of the initial volume. The resulting concentrate wasextracted with CH₂Cl₂, then the organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. Yield: 0.27 g ofcompound 9.

b. Preparation of Compound 10

A solution of3-[1-(4-fluoro-3-trifluoromethyl-phenyl)propyl]-2-mercapto-3H-imidazole-4-carbonylchloride (prepared according to A5) (0.0003 mol) in THF (p.a., dried onmolecular sieves) (1 ml) was added in one portion to stirring NH₃ (1 ml)and the reaction mixture was stirred overnight. H₂O was added and themixture was extracted with CH₂Cl₂. The organic layer was separated, thenevaporated. The residue was dissolved in acetone (5 ml) and treated witha SO₂-flow for 15 minutes. The solvent was evaporated and the residuewas purified by reversed phase high-performance liquid chromatography.The product fractions were collected and the solvent was evaporated.CH₂Cl₂ (6 ml) and an aq. K₂CO₃ solution. (1 ml, 10%) were added, thenthe mixture was stirred for 5 minutes and filtered over an ISOLUTE HM-Ncartridge. The filtrate was evaporated. Yield: 0.0289 g of compound 10.

Example B6 Preparation of compound 11

A mixture of intermediate 14 (prepared according to A5) (0.00126 mol) inpyrrolidine (0.00599 mol) was stirred in DMF (q.s.) for 4 hours at roomtemperature. The solvent was evaporated and the residue was stirred inacetone (50 ml), then treated with SO₂ for 10 minutes. The acetone wasevaporated and the concentrate was purified by reversed phasechromatography. The product fractions were collected and the solvent wasevaporated to fifty percent less of the initial volume. The resultingconcentrate was extracted with CH₂Cl₂, then the organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated.Yield: 0.180 g of compound 11.

Example B7 a. Preparation of Compound 12

A solution of3-[1-(4-fluoro-3-trifluoromethyl-phenyl)propyl]-2-mercapto-3H-imidazole-4-carbonylchloride (prepared according to A5) (0.0003 mol) in THF (p.a., dried onmolecular sieves) (1 ml) was added in one portion to stirring EtOH, p.a.(1 ml) and the reaction mixture was stirred overnight. The solvent wasevaporated and the residue was stirred in CH₂Cl₂/H₂O. The organic layerwas separated, then evaporated. The residue was dissolved in acetone (5ml) and treated with a SO₂-flow for 15 minutes. The solvent wasevaporated and the residue was purified by reversed phasehigh-performance liquid chromatography. The product fractions werecollected and the solvent was evaporated. CH₂Cl₂ (6 ml) and an aq. K₂CO₃solution. (1 ml, 10%) were added, then the mixture was stirred for 5minutes and filtered over an ISOLUTE HM-N cartridge. The filtrate wasevaporated. Yield: 0.0369 g of compound 12.

b. Preparation of Compound 61

A solution of3-[1-(4-fluoro-3-trifluoromethyl-phenyl)propyl]-2-mercapto-3H-imidazole-4-carbonylchloride (prepared according to A5) (0.0003 mol) in THF (p.a., dried onmolecular sieves) (1 ml) was added in one portion to stirring1,2-ethanediol (1 ml) and the reaction mixture was stirred overnight.H₂O was added and the mixture was extracted with CH₂Cl₂. The organiclayer was separated, then evaporated. The residue was dissolved inacetone (5 ml) and treated with a SO₂-flow for 15 minutes. The solventwas evaporated and the residue was purified by reversed phasehigh-performance liquid chromatography. The product fractions werecollected and the solvent was evaporated. CH₂Cl₂ (6 ml) and an aq. K₂CO₃solution. (1 ml, 10%) were added, then the mixture was stirred for 5minutes and filtered over an ISOLUTE HM-N cartridge. The filtrate wasevaporated. Yield: 0.0215 g of compound 61.

Example B8 Preparation of Compound 13

A mixture of intermediate 16 (prepared according to A6.b) (0.000356 mol)in CH₂Cl₂ p.a. (2 ml) was stirred under N₂-atm., carbonothioicdichloride (0.00045 mol), then N,N-diethylethanamine (0.125 ml) wasadded and the reaction mixture was stirred for 1.5 hour at roomtemperature. The mixture was quenched with H₂O and extracted withCH₂Cl₂. The organic layer was separated, filtered and the solvent wasevaporated. The residue was purified by reversed phase high-performanceliquid chromatography. The product fractions were collected and theorganic solvent was evaporated. The aqueous concentrate was extractedwith CH₂Cl₂, then the organic layer was separated, filtered and thesolvent was evaporated. Yield: 0.0072 g of compound 13.

Example B9 Preparation of Compound 14

NaOMe in MeOH (0.4 ml) was added to a solution of intermediate 18(prepared according A7.b) (0.0001 mol) in methanol, p.a. (1.5 ml) andthe reaction mixture was stirred under N₂-flow for 18 hours at roomtemperature. The mixture was quenched with acidic water and extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by filtrationover a Flash Tube (eluent: CH₂Cl₂), then the product fractions werecollected, taken up in CH₂Cl₂/CH₃OH and the solvent was evaporated.Yield: 0.0136 g of compound 14.

Example B10 Preparation of compound 16 and 17

Compound 15

(prepared according to B1.a or B1.b) (0.001 mol) was separated andpurified by chiral column chromatography over a ProChrom D.A.C. column(I.D. 5 cm; 500 g AD chiral phase; Injection: 360 mg in 1×35 ml ofethanol; eluent: Ethanol (isocratic)). Two product fraction groups werecollected and their solvent was evaporated. Yield: 0.156 g of compound16 ((A)=(+)-(R)) and 0.153 g of compound 17 ((B)=(−)-(S)).

Example B11 Preparation of Compound 16

NaH, CH₃OH (0.005 mol) was added to a mixture of intermediate 20(prepared according to A8.b) (0.00427 mol) and formic acid methyl ester(1 g) in THF (20 ml). The mixture was stirred for 24 hours at roomtemperature. The mixture was concentrated by evaporation and theconcentrate was diluted with water and washed with EtO₂. A mixture ofHCl (5 ml) and KCN (1 g) in methanol (25 ml) was added to the aqueouslayer and the resulting reaction mixture was stirred and refluxedovernight. The gummy solid was separated from the water layer and takenup into CH₂Cl₂. The organic solution was dried, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel. The product fractions were collected and the solvent wasevaporated. Yield: 0.50 g of compound 16 (R-isomer).

Example B12 Preparation of Compound-18

A mixture of compound 15

(prepared according to B1.a or B1.b) (0.00032 mol) in LiBEt₃, 1 M(superhydride) (2.5 ml) and THF (2 ml) was stirred for 2 hours at roomtemperature. Methanol was added, and then evaporated again. The residuewas purified by reversed-phase HPLC (gradient elution). The productfractions were collected and the solvent was evaporated. Yield: 0.0142 gof compound 18.

Example B13 Preparation of Compounds 19 and 20

Compound 5 (prepared according to B2.c) (0.00054 mol) was reacted withNH₄OH (q.s.) in a closed vessel for 18 hours at 100° C., then thesolvent was evaporated and the residue was purified by reversed phasehigh-performance liquid chromatography. Two product fraction groups werecollected and each solvent was evaporated. Yield Fraction group 1: 0.075g of compound 19. Yield Fraction group 2: 0.080 g of compound 20.

Example B14 a. Preparation of Compound 22

A mixture of compound 21

(prepared according to B1.a or B1.b) (0.0128 mol) in NaOH (25%) (50 ml)was stirred for 36 hours, then the solution was treated with HCl (conc.)at 0° C. The resulting precipitate was filtered off and dried (vac.).Yield: 3.2 g of compound 22.

b. Preparation of Compound 23

A solution of compound 15

(prepared according to B1.a or B1.b) (0.004 mol) in NaOH (1N) (7.5 ml),CH₃OH, p.a. (10 ml) and THF, p.a. (20 ml) was stirred at roomtemperature for 20 hours, then stirred for 5 days at 75° C. Extra NaOH(1N) (7.5 ml) was added and the reaction mixture was stirred for 1 hourat 75° C., then the mixture was allowed to reach room temperature. H₂O(45 ml), then Et₂O (50 ml) was added and the reaction mixture wasstirred for 30 minutes. The aqueous layer was separated, washed withEtOAc/Hexane (2×50 ml, 1/1) and acidified with HCl (1N) to pH 3. Themixture was extracted with CH₂Cl₂/CH₃OH (95/5), then the organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue was dissolved in Et₂O/Hexane/CH₂Cl₂ (1/1/1) and concentratedat 60° C. (without vacuum) until crystallisation started, then themixture stood for 30 minutes. The precipitate was filtered off, washedwith Hexane/Et₂O (3/1) and dried (vac., 50° C.), then dried with vacuumpump for 5 hours. Yield: 0.55 g of compound 23 (41.5%)

Example B15 Preparation of Compound 69

A mixture of compound 46

(prepared according to B2.a/B2.b) (0.00072 mol) in CH₃NH₂ (aqueoussolution) (5 ml) was stirred for 18 hours at 100° C. in a closed vessel,then the reaction mixture was cooled and the solvent was evaporatedunder N₂-flow. The residue was purified by reversed phasehigh-performance liquid chromatography. The product fractions werecollected and the solvent was evaporated to fifty percent less of theinitial volume. The concentrate was extracted with CH₂Cl₂, the organiclayer was separated, dried and the solvent was evaporated. Yield: 0.180g of compound 69.

Example B16 Preparation of Compound 77

A mixture of compound 4 (0.0005 mol) in hydrazine monohydrate (1 ml) andH₂O (4 ml) was stirred in a closed vessel for 20 hours at 100° C. Thesolvent was evaporated and then the resulting residue was used. Yield:0.108 g of compound 77.

Example B17 Preparation of Compound 78

A solution of intermediate 13 (0.0158 mol) in THF p.a. dried onmolecular sieves (60 ml) was stirred under N₂ and then ethanedioic acid,bis(1,1-dimethylethyl) ester (0.0238 mol) was added followed by2-methyl-2-propanol sodium salt (0.019 mol). The reaction mixture wasstirred for 4 hours at room temperature and extra 2-methyl-2-propanolsodium salt (0.4 g) was added. The mixture was stirred for 2 hours atroom temperature and the solvent was evaporated. The residue wasdissolved in CH₃OH (40 ml) and a solution of thiocyanic acid, potassiumsalt (0.0474 mol) in H₂O (20 ml) was added, then HCl 36% (2 ml) wasadded and the reaction mixture was stirred for 18 hours at roomtemperature. The mixture was further stirred at 50° C. for 24 hours,poured out into ice-water (150 ml) and extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered off and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 99.5/0.5). The product fractions werecollected and the solvent was evaporated. The residue was purified byreversed phase high-performance liquid chromatography (Standardgradient). The product fractions were collected and the organic solventwas evaporated. Precipitation occurred, so the aqueous concentrate wasfiltered. The filtrate was extracted with CH₂Cl₂, dried (MgSO₄),filtered off and the solvent was evaporated. The residue was stirred inDIPE, then the resulting solids were filtered off, washed and dried(vac.) at 50° C. Yield: 0.28 g of compound 78, melting point172.7-175.2° C.

Example B18 Preparation of Compound 79

2-methyl-2-propanol potassium salt (0.039 mol) was added portionwise toa mixture of intermediate 29 (0.0263 mol) and formic acid, methyl ester(10 ml) in THF (150 ml), stirred at 0° C. The mixture was stirred for 30minutes at 0° C. Thiocyanic acid, potassium salt (3 g) was added. HClconcentrated was added until the pH of the reaction mixture reachedpH=1. The reaction mixture was stirred and refluxed for 48 hours, thencooled, diluted with water, and extracted with CH₂Cl₂. The separatedorganic layer was washed with water, dried, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The product fractions werecollected and the solvent was evaporated. Yield: 6.4 g of compound 79(70%) (S(−)-isomer) optical rotation: [α]₂₀ ^(D)=−251.6° (c=0.26 CHCl₃).

Example B19 Preparation of Compound 80

2-methyl-2-propanol sodium salt (2.5 g) was added portionwise to amixture of intermediate 31 (0.0066 mol) in formic acid, methyl ester (5ml) and THF (q.s.) at 0° C. and the reaction mixture was left to standovernight at room temperature, then the mixture was diluted with etherand water. The aqueous layer was treated with thiocyanic acid, potassiumsalt (q.s.), HCl (q.s.) and with CH₃OH (q.s.) and the resulting mixturewas heated for 20 hours, cooled and the solvent was evaporated. Theresidue was purified by reversed phase high-performance liquidchromatography. The pure fractions were collected and the solvent wasevaporated. Yield compound 80.

Example B20 Preparation of Compound 81

A mixture of compound 106 (prepared according to B6) (0.0008 mol) in THF(10 ml) was stirred at 0-5° C. on an ice bath and chloromethyl-magnesium20% in THF (0.002 mol) was added dropwise, then the reaction mixture wasstirred for 1 hour and extra chloromethyl-magnesium 20% in THF (0.0044mol) was added dropwise. The mixture was stirred for 1 hour and againextra chloromethyl-magnesium 20% in THF (0.002 mol) was added dropwise,then the reaction mixture was stirred for 1 hour and 1N HCl (10 ml) wasadded dropwise under cooling with ice. Water was added and the mixturewas extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue wasdissolved in 2-propanone (p.a.) and a stream of SO₂ was passed throughthe solution for 20 minutes. The solvent was evaporated and the residuewas purified by Flash column chromatography (eluent: EtOAc). The productfractions were collected and dissolved in CH₂Cl₂/CH₃OH (90/10), then themixture was filtered and the filtrate's solvent was evaporated Yield:0.060 g of compound 81.

Example B21 Preparation of Compound 82

A mixture of compound 7 (0.0024 mol) andN-ethyl-N-(1-methylethyl)-2-propanamine (0.005 mol) in pyridine (25 ml)was stirred at 80° C. on an oil bath and hydrogen sulfide (gas) waspassed through the solution for 90 minutes, then N₂ was passed throughfor 2 hours in order to remove the hydrogen sulfide. The solvent wasevaporated and the residue was dissolved in CH₂Cl₂. The solution waswashed with H₂O and with 1N HCl. The organic layer was separated, dried(MgSO₄), filtered off and the solvent was evaporated. The residue waspurified over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The productfractions were collected and the solvent was evaporated. The residue wasstirred in DIPE, then the resulting precipitate was filtered off anddried. Yield: 0.340 g of compound 82.

Example B22 Preparation of Compound 83

A mixture of compound 81 (0.0003 mol) in CH₃OH (3 ml) was stirred atroom temperature and sodium hydroborate (0.0003 mol) was added, then thereaction mixture was stirred overnight at room temperature. Theresulting mixture was acidified with 1N HCl and the solvent wasevaporated. The residue was dissolved in CH₂Cl₂ and washed with H₂O. Theorganic layer was separated, dried (MgSO₄), filtered off and the solventwas evaporated. The residue was purified by reversed phase (NaHCO₃)high-performance liquid chromatography (standard gradient). The productfractions were collected and the solvent was evaporated. Yield: compound83.

Example B23 a) Preparation of Compound 84

A mixture of compound 68

(0.000257 mol) in SOCl₂ (5 ml) was stirred overnight at roomtemperature, then the solvent was evaporated and co-evaporated withtoluene (p.a.). The resulting residue was used as such in the nextreaction step. Yield: compound 84.

b) Preparation of Compound 85

A solution of compound 84 (0.000257 mol) in THF, p.a. dried on molecularsieves (10 ml) was stirred under N₂ at room temperature, then sodiumhydroborate (0.00077 mol) was added portionwise and the reaction mixturewas stirred for 1 hour at room temperature. Water (15 ml) was added andthen HCl (1N) was added (foaming) until pH: 2. The mixture was extractedwith CH₂Cl₂ and the organic layer was separated, then dried (MgSO₄) andfiltered. The solvent was evaporated and the residue was purified byreversed phase high-performance liquid chromatography. The productfractions were collected and the organic solvent was evaporated. Theaqueous concentrate was extracted with CH₂Cl₂, then the organic layerwas separated, dried (MgSO₄), filtered off and the solvent wasevaporated. Yield: 0.028 g of compound 85.

Example B24 Preparation of Compound 86

Compound 84 (0.000196 mol) was dissolved in THF, p.a. dried on molecularsieves (1 ml) under N₂ and the solution was added to stirring aqueousNH₃ solution (1 ml), then the reaction mixture was stirred for 1 hourand water (5 ml) was added. CH₂Cl₂/CH₃OH (95/5, 5 ml) was added, thensome crushed ice was added and concentrated HCl was added dropwise untila clear biphasic solution was obtained. The organic layer was evaporatedand the residue was stirred in 2-propanone (5 ml, p.a.). The mixture wastreated with SO₂ (gas) for 10 minutes and the solvent was evaporated.The residue was purified by reversed phase high-performance liquidchromatography. The product fractions were collected and the organicsolvent was evaporated. The aqueous concentrate was extracted withCH₂Cl₂ and the organic layer was separated, finally the solvent wasevaporated. Yield: 0.025 g of compound 86.

Example B25 Preparation of Compound 87

Compound 84 (0.000196 mol) was dissolved in THF, p.a. dried on molecularsieves (1 ml) under N₂ and the solution was added to stirringmethylamine 40% (1 ml), then the reaction mixture was stirred for 1 hourand ice-water (5 ml) was added. CH₂Cl₂/CH₃OH (95/5) (5 ml) was added andthen concentrated HCl was added dropwise until a clear biphasic solutionwas obtained. The separated organic layer was evaporated and the residuewas stirred in 2-propanone (5 ml). The mixture was treated with SO₂(gas) for 10 minutes and the solvent was evaporated. The residue waspurified by reversed phase high-performance liquid chromatography. Theproduct fractions were combined and the organic solvent was evaporated.The aqueous concentrate was extracted with CH₂Cl₂ and the separatedorganic layer was evaporated. Yield: 0.0122 g of compound 87.

Example B26 Preparation of Compound 88

Trifluoroacetic acid (2 ml) was added to a stirring solution of compound78 (0.0015 mol) in CH₂Cl₂ p.a. (25 ml), then the reaction mixture wasstirred for 18 hours at room temperature (precipitation) and left tostand for 24 hours. The resulting precipitate was filtered off, washedwith a small amount of CH₂Cl₂ and a lot of DIPE and finally dried(vacuum) at 50° C. Yield: 0.45 g of compound 88.

Example B27 Preparation of Compound 89

Intermediate 24 (0.003 mol) was added dropwise to a cold (−78° C.)solution of N-(1-methylethyl)-2-propanamine lithium salt (0.0036 mol) inTHF (5 ml), after 30 minutes Methoxy-acetyl chloride (0.006 mol) wasadded to the reaction mixture and stirred for 1 hour at roomtemperature. The mixture was quenched with an aqueous NH₄Cl solution andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered off and the solvent was evaporated. The residue was taken up inmethanol (50 ml), thiocyanic acid, potassium salt (1 g) and concentratedHCl (1 ml) and the resulting mixture was heated for 18 hours at 70° C.The solvent was evaporated and the residue was extracted with CH₂Cl₂,then the separated organic layer was dried and the solvent wasevaporated. The residue was purified by reversed phase high-performanceliquid chromatography; the product fractions were collected and thesolvent was evaporated. Yield: 0.250 g of compound 89.

Example B28 Preparation of Compounds 90, 91 and 92

A mixture of compound 55

(0.0015 mol) (prepared according to B2.a/B2.b) in NH₃/H₂O (12 ml) wasstirred in a closed vessel at 100° C. for 18 hours and then the solventwas evaporated. The residue was stirred again in extra NH₃/H₂O (12 ml)in a closed vessel at 110° C. for 18 hours. The residue (0.6 g) waspurified by reversed phase high-performance liquid chromatography. Theproduct fractions were collected and the solvent was evaporated. Yieldcompound 92, compound 91 and compound 90.

Table 1, 2 and 3 list the compounds of formula (I) which were preparedaccording to one of the above examples (Ex. No.).

In the right column headed by “Physical data”, the mass value of thecompounds together with the retention time is indicated. Said data weregenerated as described below:

The HPLC gradient was supplied by a Waters Alliance HT 2790 system witha column heater set at 40° C. Flow from the column was split to a Waters996 photodiode array (PDA) detector and a Waters-Micromass ZQ massspectrometer with an electrospray ionization source operated in positiveand negative ionization mode. Reversed phase HPLC was carried out on aXterra MS C18 column (3.5 μm, 4.6×100 mm) (12 minutes column) with aflow rate of 1.6 ml/minutes. Three mobile phases (mobile phase A: 95% 25mM ammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobilephase C: methanol) were employed to run a gradient condition from 100% Ato 50% B and 50% C in 6.5 minutes, to 100% B in 1 minute, 100% B for 1minute and reequilibrate with 100% A for 1.5 minute. An injection volumeof 10 μL was used.

Mass spectra were acquired by scanning from 100 to 1000 in 1 s using adwell time of 0.1 s. The capillary needle voltage was 3 kV and thesource temperature was maintained at 140° C. Nitrogen was used as thenebulizer gas. Cone voltage was 10 V for positive ionzation mode and 20V for negative ionization mode. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system.

TABLE 1

Co. no. Ex. no. R₁ R_(2a) R_(2b) R2c R₃ 24 B1a/B1b n-propyl Cl H H

25 B1a/B1b n-propyl H Cl H

26 B1a/B1b methyl Cl H H

27 B1a/B1b methyl CH₃ CH₃ H

28 B1a/B1b H H OCH₃ H

29 B1a/B1b H Cl H H

31 B1a/B1b methyl H Cl H

32 B1a/B1b methyl Cl Cl H

33 B7 ethyl Cl Cl H

34 B6 ethyl Cl Cl H

18 B12 ethyl Cl Cl H —CH₂OH 23 B14b ethyl Cl Cl H

35 B1a/B1b n-propyl Cl Cl H

21 B1a/B1b ethyl F F H

16 B10/B11 ethyl Cl Cl H

17 B10 ethyl Cl Cl H

15 B1a/B1b ethyl Cl Cl H

76 B1a/B1b ethyl Br Br H

22 B14a ethyl F F H

36 B6 ethyl F F H

6 B3 ethyl Cl Cl H

37 B2a/B2d ethyl Cl Cl H

74 B14a ethyl Br Br H

7 B4 ethyl Cl Cl H —C≡N 38 B6 ethyl Cl Cl H

75 B3 ethyl Cl Cl H

8 B4 ethyl Cl Cl H

39 B2a/B2b ethyl F F H

40 B14a ethyl Cl Cl H

1 B1a/B1b ethyl CF₃ F H

3 B2a/B2b ethyl CF₃ F H

9 B5a ethyl F F H

66 B7a ethyl F F H

30 B6 ethyl F F H

41 B6 ethyl F F H

42 B6 ethyl F F H

43 B1a/B1b ethyl F CF₃ H

11 B6 ethyl F F H

44 B6 ethyl F F H

45 B6 ethyl F F H

46 B2a/B2b n-propyl Cl Cl H

47 B2a/B2b H Cl Cl H

67 B14a ethyl CF₃ F H

14 B9 ethyl Cl Cl H H 5 B2c ethyl Cl Cl H —C≡N 48 B2a/B2b ethyl F CF₃ H

12 B7 ethyl CF₃ F H

61 B7b ethyl CF₃ F H

49 B6 ethyl CF₃ F H

10 B5b ethyl CF₃ F H

62 B7b ethyl CF₃ F H

19 B13 ethyl Cl Cl H —C≡N 20 B13 ethyl Cl Cl H

71 B14a ethyl Cl Cl H H 64 B7a ethyl Cl Cl H H 50 B2a/B2b ethyl Br Br H

63 B7b ethyl Cl Cl H H 51 B5a ethyl Cl Cl H H 52 B6 ethyl Cl Cl H H 53B6 ethyl Cl Cl H H 54 B5a methyl Cl Cl H

55 B2a/B2b methyl Cl Cl H

65 B7a ethyl CF₃ F H

56 B2a/B2b phenyl Cl Cl H

69 B15 n-propyl Cl Cl H

57 B13 ethyl Br Br H

70 B15 ethyl Cl Cl H —C≡N 58 B10/B11 ethyl Cl Cl H

59 B10/B11 ethyl Cl Cl H

60 B2a/B2b n-propyl Cl Cl H

72 B1a/B1b

Cl Cl H

2 B1a/B1b

Cl Cl H

68 B2d ethyl Cl Cl H

4 B2a/B2b

Cl Cl H

73 B2a/B2b

Cl Cl H

79 B18 ethyl Cl Cl H

13 B8 methyl Cl Cl H —C≡N 93 B1a/B1b

Cl Cl H

94 B1a/B1b

Cl Cl H

95 B6 ethyl Cl Cl H

84 B23a ethyl Cl Cl H

96 B6 ethyl Cl Cl H

97 B1a/B1b ethyl CH₃ CH₃ H

98 B13 methyl Cl Cl H

92 B28 methyl Cl Cl H

91 B28 methyl Cl Cl H H 90 B28 methyl Cl Cl H

99 B2a/B2d ethyl CH₃ CH₃ H

100 B2a/B2d

Cl Cl H

101 B1a/B1b ethyl

H

102 B6 ethyl Cl Cl H

103 B14a

Cl Cl H

104 B5a

Cl Cl H

105 B6 ethyl Cl Cl H

106 B6 ethyl Cl Cl H

81 B20 ethyl Cl Cl H

85 B23b ethyl Cl Cl H

86 B24 ethyl Cl Cl H

87 B25 ethyl Cl Cl H

107 B15 ethyl Cl Cl H

108 B6 ethyl Cl Cl H

109 B6 ethyl Cl Cl H

110 B6 ethyl Cl Cl H

89 B27 ethyl Cl Cl H

111 B6 ethyl F F H

112 B6 ethyl F F H

113 B6 ethyl Cl Cl H

114 B6 ethyl Cl Cl H

115 B6 ethyl Cl Cl H

116 B6 ethyl Cl Cl H

117 B6 ethyl Cl Cl H

118 B1a/B1b ethyl F H F

119 B6 ethyl Cl Cl H

120 B6 ethyl Cl Cl H

121 A5 ethyl Cl Cl H

122 B2d ethyl Cl Cl H

123 B1a/B1b ethyl H Cl H

124 B2a ethyl F H F

125 B20 ethyl F F H

126 B6 ethyl F H F

127 B6 ethyl F H F

82 B21 ethyl Cl Cl H

128 B1a/B1b ethyl Cl H Cl

129 B1a/B1b ethyl CF₃ H CF₃

130 B2a ethyl Cl H Cl

131 B6 ethyl CF₃ H CF₃

132 B2a ethyl CF₃ H CF₃

133 B6 ethyl Cl H Cl

134 B1a/B1b ethyl

H H

135 B1a/B1b ethyl F F F

136 B2a/B2b ethyl

H H

137 B2d ethyl F F H

138 B6 ethyl Br Br H

139 B6 ethyl

H H

140 B1a/B1b

Cl Cl H

141 B14a

Cl Cl H

142 B6 ethyl F F H

143 B6 ethyl F F F

144 B2d propyl Cl Cl H

145 B2d propyl Cl Cl H

146 B2d propyl Cl Cl H

147 B1a/B1b

Cl Cl H

148 B2d ethyl F F F

149 B6 propyl Cl Cl H

83 B22 ethyl Cl Cl H

150 B2a

CL Cl H

151 B20 ethyl Cl Cl H

152 B14a ethyl Cl Cl H

153 B6 ethyl F H F

154 B14a ethyl F H F

155 B14a ethyl

H H

156 B6 ethyl F H F

157 B14a ethyl F F F

158 B2d ethyl F F H

159 B6 ethyl Cl Cl H

88 B26 ethyl Cl Cl H —C≡N 78 B17 ethyl Cl Cl H —C≡N Physical dataretention Co. time no. R₄ [M⁺]* (minutes) other 24 H 25 H 26 H 27 H 28 H29 H 31 H 32 H 330 3.76 33 H 373 9.67** 34 H 344 3.48 18 H 23 H 35 H 3584.26 21 H 313 8.14** 16 H 344 9.10 +229.9°¹ 17 H 344 9.10 −211.7°² 15 Hmp. 166° C. 76 H 22 H 298 4.55 36 H 311 6.99 6 CH₃ 358 9.27** 37

403 4.55 74 H 419 6.26 7 H 312 5.71 38 CH₃ 357 7.76 75 CH₃ 8 H 330 4.9439

370 4.96 40

374 4.4 1 H 363 5.7 3

421 5.35 9 H 297 4.9 66 H 326 4.95 30 H 41 H 367 4.8 42 H 365 5.44 43 H363 5.76 11 H 351 5.02 44 H 353 5.59 45 H 353 5.57 46

384 4.77 47

375 5.12 67 H 349 3.63 14

345 5.73 5

370 5.05 48

421 5.52 12 H 378 5.79 61 H 393 5.13 49 H 362 4.92 10 H 348 4.66 62 H462 5.68 19

355 4.29 20

373 4.45 71

331 4.43 64

373 6.05 50

492 5.36 63

375 5.17 51

330 4.86 52

344 4.99 53

399 4.61 54 H 315 4.65 55

388 5.43 65 H 56

450 5.93 69

458 5.1 57

460 5.4 70

368 4.26 58 H 329 5.02 A-isomer; +210.5°³ 59 H 329 5.02 B-isomer;−202.17°⁴ 60

72 H 398 6.82 2 H 356 5.99 68

4

414 5.81 73

456 6.64 79 H 345 5.94 S-(−) 13 —C≡N 93 H 374 5.67 94 H 361 5.49 95 H343 (−) 4.65 84

96

445 4.53 97 H 305 5.40 98

359 3.69 92

374 3.82 91

316 4.39 90

374 4.53 99

363 5.28 100

419 5.28 101 H 337 4.41 102

431 4.64 103 H 347 3.52 104 H 346 4.56 105 H 374 4.81 106 H 374 5.58 81H 329 5.69 85

375 5.30 86

386 (−) 4.96 87

402 5.09 107

401 4.60 108

456 5.51 109

458 4.89 110

432 4.85 89

389 6.06 111 H 342 4.56 112 H 342 3.89 113

374 4.80 114

388 5.12 115

418 4.74 116

428 5.55 117

457 5.33 118 H mp. 187- 189° C. 119 H 387 4.74 120 H 373 4.69 121 H 122

445 6.44 123 H 311 5.31 124

371 5.37 125 H 295 *** 5.08 126 H 298 4.22 127 H 342 4.18 82 H 346 5.45128 H mp. 159- 163° C. 129 H mp. 151- 155° C. 130

mp. 160- 165° C. 131 H 396 *** 4.65 132

mp. 107- 109° C. 133 H 328 *** 4.25 134 H 369 5.06 135 H 329 *** 4.68136

427 5.58 137

413 5.61 138 H mp. 128° C. 139 H 325 5.28 140 H mp. 222- 226° C. 141 Hmp. 236- 242° C. 142

356 4.23 143 H 316 4.26 144

145

146

459 7.01 147 H 399 6.12 148

389 5.14 149

402 5.39 83 H 331 5.01 150

521 5.96 151 H 343 5.96 152

376 3.65 153 H 154 155 H 355 3.89 156 157 H 315 2.87 *** 158

355 *** 4.31 159 H 388 3.69 88

354 *** 5.22 78

412 4.70 *[M⁺] defines the mass of the compound **retention timeobtained on a 18 minutes column. ***Mass −1, only response in negativemode. ¹[α]₂₀ ^(D) at concentration of 2.40 g/100 ml in CHCl₃; ²[α]₂₀^(D) at concentration of 3.42 g/100 ml in CHCl₃; ³[α]₂₀ ^(D) atconcentration of 0.2152 g/100 ml in CH₃OH; ⁴[α]₂₀ ^(D) at concentrationof 0.2216 g/100 ml in CHCl₃

TABLE 2

Physical data retention Co. Ex. time no. no. R₁ R_(2a) R_(2b) R₃ R₄ R₅[M⁺]* (minutes) other 80 B19 CH₃ Cl Cl

H CH₃ 343 *** 4.81 *[M⁺] defines the mass of the compound

TABLE 3

Physical data retention Co. Ex. time no. no. R₁ R_(2a) R_(2b) R_(2c)[M⁺]* (minutes) other 77 B16

Cl Cl H 383 4.65 160 B16 CH₃ Cl Cl H 383 3.84 161 B16

Cl Cl H 417 4.68 162 B16

Cl Cl H 423 5.34 163 B16 ethyl Cl H Cl 373 4.24 164 B16 ethyl Cl Cl H371 4.38 165 B16 ethyl F F H 339 3.69 *[M⁺] defines the mass of thecompound

C. Pharmacological Example

Inhibition of MCP-1 induced Ca-flux in Human THP-1 Cells

MCP-1 binding to the CCR2 receptor induces a rapid and transientintracellular release of Ca²⁺ (secondary messenger) in several celllines (Charo et al, PNAS 1994). Free Ca²⁺ levels can be measured using aCa²⁺ sensitive dye. When the CCR2 receptor is blocked with a CCR2receptor antagonist, the MCP-1 induced release of Ca²⁺ is inhibited.

Human THP-1 cells (monocytic cell line, ATCC TIB-202) were cultured inRPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 1%L-Glutamine, penicillin (50 U/ml) and streptomycin (50 μg/ml) (all GIBCOBRL, Gent). After centrifugation, cells were loaded for 30 minutes withthe Ca²⁺ sensitive fluorescent dye Fluo-3 AM (Molecular Probes, Leiden,Netherlands) (2 million cells/ml in RPMI medium containing 4 μM Fluo-3AM, 20 mM HEPES, 0.1% Bovine Serum Albumin (BSA) and 5 mM probenecid).Excess dye was removed by 3-fold washing with buffer (5 mM HEPES, 140 mMNaCl, 1 mM MgCl₂, 5 mM KCl, 10 mM glucose, 2.5 mM probenecid, 1.25 mMCaCl₂, 0.1% BSA; all further incubations were done in this buffer).Cells were plated at a density of 150 000 cells/well in dark-wall96-well plates (Costar, Cambridge, Mass.) and sedimented bycentrifugation (1 minute). The cells were pre-incubated for 20 minuteswith test compound. Then, 10⁻⁷ M hMCP-1 (Bachem, Bubendorf, Switserland)was added. Changes in intracellular free Ca²⁺ concentration weremeasured using the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices, Munchen, Germany). Fluorescence was recorded every second from10 seconds before the addition of the MCP-1 till 2 minutes after theaddition (first minute: 60 records with 1 second intervals, secondminute 20 records with 3 second intervals). The maximal fluorescenceobtained during this time frame was used for further calculations.

Table 4 reports pIC₅₀ values obtained in the above-described test forcompounds of formula (I). pIC₅₀ defines —log IC₅₀ wherein IC₅₀ is themolar concentration of the test compound which inhibits 50% of specificMCP-1 induced Ca²⁺ flux.

TABLE 4 CoNo pIC50 24 6.05 25 5.45 31 5.43 32 6.59 33 6.58 34 6.66 235.48 35 6.86 21 5.99 16 5.99 17 7.06 15 6.72 76 6.59 36 5.65 6 6.58 378.014 74 5.47 7 6.155 75 6.58 8 7.456 39 8.14 40 5.86 1 6.03 3 7.76 96.333 66 6.125 43 5.7 44 5.505 45 5.605 46 8.005 47 7.45 67 5.63 14 6.455 7.4 48 7.05 12 6.46 61 6.64 49 5.64 10 6.69 62 5.99 19 6.92 20 7.24550 7.53 63 5.99 51 5.75 52 5.09 54 5.96 55 7.9 56 6.693 69 6.405 576.775 70 6.59 59 7.363 60 5.61 2 5.67 68 6.075 73 6.357 4 7.555 94 6.51577 6.48 160 6.16 161 5.19 162 5.55 95 6.61 96 6.73 98 5.69 91 5.09 906.877 99 6.465 100 7.49 104 7.067 105 6.887 106 5.75 81 6.88 85 6.815 867.302 87 7.48 107 6.45 108 6.95 109 5.94 110 6.95 89 6.97 113 6.62 1145.75 115 5.92 118 5.08 119 6.06 120 5.98 123 5.33 124 7.19 80 5.32 1305.78 135 5.37 137 5.6 138 6.755 142 7.23 143 6.78 148 7.475 164 6.28 1656.145 149 7.49 150 6.33 151 6.525 159 5.78 88 6.76 78 6.09

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled) 11.The method for treating diseases mediated through activation of the CCR2receptor comprising administering to a person in need thereof atherapeutically effective amount of a compound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein R₁represents hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl or heteroaryl; each R₂ independentlyrepresents halo, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano, aminocarbonyl, amino,mono- or di(C₁₋₄alkyl)amino, nitro, aryl or aryloxy; R₃ representshydrogen, cyano, C₁₋₆alkyl optionally substituted with hydroxy orC₁₋₆alkyloxy, C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b), C(═S)—NR_(7a)R_(7b),S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₅; R₄ represents hydrogen, cyano,C₁₋₆alkyl optionally substituted with hydroxy or C₁₋₆alkyloxy,C(═O)—O—R₆, C(═O)—NR_(7a)R_(7b), C(═S)—NR_(7a)R_(7b),S(═O)₂—NR_(7a)R_(7b) or C(═O)—R₈; or R₃ and R₄ taken together may form abivalent radical of formula —C(═O)—NH—NH—C(═O)—; R₆ represents hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl, aryl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl;wherein pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, morpholinyl or thiomorpholinyl may optionally besubstituted with C₁₋₄alkyl; R_(7a) and R_(7b) each independentlyrepresent hydrogen, C₁₋₆alkyl, amino, mono- or di(C₁₋₄alkyl)amino,arylNH—, aminoC₁₋₆alkyl, mono- or di(C₁₋₄alkyl)amino C₁₋₆alkyl,C₁₋₆alkylcarbonylamino, aminocarbonylamino, C₁₋₆alkyloxy, —NH—C(O)—H orhydroxyC₁₋₆alkyl; or R_(7a) and R_(7b) taken together with the nitrogento which they are attached form pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl orpiperazinyl substituted with C₁₋₆alkyl; R₈ represents hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,polyhaloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- ordi(C₁₋₄alkyl)aminocarbonylC₁₋₆alkyl or aryl; R₅ represents hydrogen orC₁₋₆alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, amino, mono- or di(C₁₋₄alkyl)amino,phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, each of said heterocycles optionally being substituted withone or two substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, cyano,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, amino, mono- ordi(C₁₋₄alkyl)amino or nitro; provided that at least one of R₃ or R₄ isother than hydrogen.
 12. (canceled)
 13. The method according to claim 11wherein the disease is an inflammatory disease.
 14. (canceled) 15.(canceled)
 16. (canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled)